Isoxazolines as inhibitors of fatty acid amide hydrolase

ABSTRACT

The present invention provides isoxazoline FAAH inhibitors of the formula (I): or pharmaceutically acceptable forms thereof, wherein each of G, Ra, Rb, Rc, and Rd are as defined herein. The present invention also provides pharmaceutical compositions comprising a compound of formula (I), or a pharmaceutically acceptable form thereof, and a pharmaceutically acceptable excipient. The present invention also provides methods for treating an FAAH-mediated condition comprising administering a therapeutically effective amount of a compound of formula (I), or pharmaceutically acceptable form thereof, to a subject in need thereof.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application claims priority to U.S. provisional patentapplication Ser. No. 61/179,283 filed May 18, 2009, the entirety ofwhich is hereby incorporated herein by reference.

BACKGROUND

Fatty acid amide hydrolase (FAAH), also referred to as oleamidehydrolase and anandamide amidohydrolase, is an integral membrane proteinresponsible for the hydrolysis of several important endogenousneuromodulating fatty acid amides (FAAs), including anadamide,oleoylethanolamide and palmitoylethanolamide, and is intimately involvedin their regulation. Because these FAAs interact with cannabinoid andvanilliod receptors, they are often referred to as “endocannabinoids” or“endovanilliods”. Initial interest in this area focused on developingFAAH inhibitors to augment the actions of FAAs and reduce pain. Furtherinvestigation found FAAH inhibitors, through interactions of the FAAswith unique extracellular and intracellular receptors, can be used totreat a variety of conditions that include, but are not limited to,inflammation, metabolic disorders (e.g., obesity-related conditions andwasting conditions such as cachexias and anorexia), disorders of thecentral nervous system (e.g., disorders associated with neurotoxicityand/or neurotrauma, stroke, multiple sclerosis, spinal cord injury,movement disorders such as basal ganglia disorders, amylotrophic lateralsclerosis, Alzheimer's disease, epilepsy, mental disorders such asanxiety, depression, learning disorders and Schizophrenia, sleepdisorders such as insomnia, nausea and/or emesis, and drug addiction),cardiac disorders (e.g., hypertention, circulatory shock, myocardialreperfusion injury and atherosclerosis) and glaucoma (Pacher et al.,“The Endocannabinoid System as an Emerging Target of Pharmacotherapy”Pharmacological Reviews (2006) 58:389-462; Pillarisetti et al., “Painand Beyond: Fatty Acid Amides and Fatty Acid Amide Hydrolase Inhibitorsin Cardiovascular and Metabolic Diseases” Drug Discovery Today (2009)597:1-14).

SUMMARY

The present invention provides isoxazoline FAAH inhibitor compounds ofthe formula (I):

or pharmaceutically acceptable forms thereof,

wherein:

each of R^(a), R^(b), and R^(c) independently is selected from —H, C₁₋₁₀alkyl and C₁₋₁₀ perhaloalkyl, R^(d) is the group -L-Z, and Z is selectedfrom 3-14 membered heterocyclyl and 5-14 membered heteroaryl;

L is a covalent bond or a divalent C₁ hydrocarbon group, wherein one,two or three methylene units of L are optionally and independentlyreplaced with one or more oxygen, sulfur or nitrogen atoms;

G is selected from —CN, —NO₂, —S(═O)R^(e), —SO₂R^(e), —SO₂NR^(f)R^(e),—PO₂R^(e), —PO₂OR^(e), —PO₂NR^(f)R^(e), —(C═O)R^(e), —(C═O)OR^(e),—(C═O)NR^(f)R^(e), —Br, —I, —F, —Cl, —OR^(e), —ONR^(f)R^(e),—ONR^(f)(C═O)R^(e), —ONR^(f)SO₂R^(e), —ONR^(f)PO₂R^(e),—ONR^(f)PO₂OR^(e), —SR^(e), —OSO₂R^(e), —NR^(f)SO₂R^(e), —OPO₂R^(e),—OPO₂OR^(e), —NR^(f)PO₂R^(e), —NR^(f)PO₂OR^(e), —OPO₂NR^(f)R^(e),—O(C═O)R^(e), —O(C═O)OR^(e), —NR^(f)R^(e), —NR^(f)(C═O)R^(e),—NR^(f)(C═O)OR^(e), —O(C═O)NR^(f)R^(e), —NR^(f)(C═NR^(f))NR^(f)R^(e),—O(C═NR^(f))NR^(f)R^(e), —NR^(f)(C═NR^(f))OR^(e), —[N(R^(f))₂R^(e)]⁺X⁻wherein X⁻ is a counterion;

each R^(e) is selected from C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl,C₃₋₁₀ carbocycyl, C₆₋₁₄ aryl, 3-14 membered heterocyclyl and 5-14membered heteroaryl; each R^(f) attached to a nitrogen atom is,independently, selected from —H, C₁₋₁₀ alkyl, or an amino protectinggroup; or R^(e) and R^(f) are joined to form an 3-14 memberedheterocyclyl ring or an 5-14 membered heteroaryl ring.

The present invention also provides pharmaceutical compositionscomprising a compound of formula (I), or a pharmaceutically acceptableform thereof, and a pharmaceutically acceptable excipient.

The present invention also provides methods for treating anFAAH-mediated condition in a subject comprising administering atherapeutically effective amount of a compound of formula (I), or apharmaceutically acceptable form thereof, to a subject in need thereof.

The details of additional embodiments of the invention are set forth inthe accompanying Detailed Description and Exemplification as describedbelow. Other features, objects, and advantages of the invention will beapparent from this description and from the claims.

DEFINITIONS

Definitions of specific functional groups ad chemical terms aredescribed in more detail below. The chemical elements are identified inaccordance with the Periodic Table of the Elements, CAS version,Handbook of Chemistry and Physics, 75^(th) Ed., inside cover, andspecific functional groups are generally defined as described therein.Additionally, general principles of organic chemistry, as well asspecific functional moieties and reactivity, are described in OrganicChemistry, Thomas Sorrell, University Science Books, Sausalito, 1999;Smith and March March's Advanced Organic Chemistry, 5^(th) Edition, JohnWiley & Sons, Inc., New York, 2001; Larock, Comprehensive OrganicTransformations, VCH Publishers, Inc., New York, 1989; and Carruthers,Some Modern Methods of Organic Synthesis, 3^(rd) Edition, CambridgeUniversity Press, Cambridge, 1987.

Certain compounds of the present invention can comprise one or moreasymmetric centers, and thus can exist in various isomeric forms, e.g.,enantiomers and/or diastereomers. The compounds provided herein can bein the form of an individual enantiomer, diastereomer or geometricisomer, or can be in the form of a mixture of stereoisomers, includingracemic mixtures and mixtures enriched in one or more stereoisomer. Incertain embodiments, the compounds of the invention are enantiopurecompounds. In certain other embodiments, mixtures of stereoisomers areprovided.

Furthermore, certain compounds, as described herein may have one or moredouble bonds that can exist as either the cis or trans, or the E or Zisomer, unless otherwise indicated. The invention additionallyencompasses the compounds as individual isomers substantially free ofother isomers, and alternatively, as mixtures of various isomers, e.g.,racemic mixtures of E/Z isomers or mixtures enriched in one E/Z isomer.

The terms “enantiomerically enriched,” “enantiomerically pure” and“non-racemic,” as used interchangeably herein, refer to compositions inwhich the percent by weight of one enantiomer is greater than the amountof that one enantiomer in a control mixture of the racemic composition(e.g., greater than 1:1 by weight). For example, an enantiomericallyenriched preparation of the (S)-enantiomer, means a preparation of thecompound having greater than 50% by weight of the (S)-enantiomerrelative to the (R)-enantiomer, more preferably at least 75% by weight,and even more preferably at least 80% by weight. In some embodiments,the enrichment can be much greater than 80% by weight, providing a“substantially enantiomerically enriched,” “substantiallyenantiomerically pure” or a “substantially non-racemic” preparation,which refers to preparations of compositions which have at least 85% byweight of one enantiomer relative to other enantiomer, more preferablyat least 90% by weight, and even more preferably at least 95% by weight.In preferred embodiments, the enantiomerically enriched composition hasa higher potency with respect to therapeutic utility per unit mass thandoes the racemic mixture of that composition. Enantiomers can beisolated from mixtures by methods known to those skilled in the art,including chiral high pressure liquid chromatography (HPLC) and theformation and crystallization of chiral salts; or preferred enantiomerscan be prepared by asymmetric syntheses. See, for example, Jacques, etal., Enantiomers, Racemates and Resolutions (Wiley Interscience, NewYork, 1981); Wilen, S. H., et al., Tetrahedron 33:2725 (1977); Eliel, E.L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); andWilen, S. H. Tables of Resolving Agents and Optical Resolutions p. 268(E. L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, Ind. 1972).

When a range of values is listed, it is intended to encompass each valueand sub-range within the range. For example “C₁₋₆ alkyl” is intended toencompass, C₁, C₂, C₃, C₄, C₅, C₆, C₁₋₆, C₁₋₅, C₁₋₄, C₁₋₃, C₁₋₂, C₂₋₆,C₂₋₅, C₂₋₄, C₂₋₃, C₃₋₆, C₃₋₅, C₃₋₄, C₄₋₆, C₄₋₅, and C₅₋₆ alkyl.

As used herein a “direct bond” or “covalent bond” refers to a singlebond joining two groups.

As used herein, alone or as part of another group, “halo” and “halogen”refer to fluorine (fluoro, —F), chlorine (chloro, —Cl), bromine (bromo,—Br), or iodine (iodo, —I).

As used herein, alone or as part of another group, “alkyl” refers to amonoradical of a straight-chain or branched saturated hydrocarbon grouphaving from 1 to 10 carbon atoms (“C₁₋₁₀ alkyl”). In some embodiments,an alkyl group has 1 to 9 carbon atoms (“C₁₋₉ alkyl”). In someembodiments, an alkyl group has 1 to 8 carbon atoms (“C₁₋₈ alkyl”). Insome embodiments, an alkyl group has 1 to 7 carbon atoms (“C₁₋₇ alkyl”).In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C₁₋₆alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms(“C₁₋₅ alkyl”). In some embodiments, an alkyl group has 1 to 4 carbonatoms (“C₁₋₄ alkyl”). In some embodiments, an alkyl group has 1 to 3carbon atoms (“C₁₋₃ alkyl”). In some embodiments, an alkyl group has 1to 2 carbon atoms (“C₁₋₂ alkyl”). In some embodiments, an alkyl grouphas 1 carbon atom (“C₁ alkyl”). In some embodiments, an alkyl group has2 to 6 carbon atoms (“C₂₋₆ alkyl”). Examples of C₁₋₆ alkyl groupsinclude methyl (C₁), ethyl (C₂), n-propyl (C₃), isopropyl (C₃), n-butyl(C₄), tert-butyl (C₄), sec-butyl (C₄), iso-butyl (C₄), n-pentyl (C₅),3-pentanyl (C₅), amyl (C₅), neopentyl (C₅), 3-methyl-2-butanyl (C₅),tertiary amyl (C₅), and n-hexyl (C₆). Additional examples of alkylgroups include n-heptyl (C₇), n-octyl (C₈) and the like. Unlessotherwise specified, each instance of an alkyl group is independentlyunsubstituted (an “unsubstituted alkyl”) or substituted (a “substitutedalkyl”) are substituted with 1, 2, 3, 4, or 5 substituents as describedherein. In certain embodiments, the alkyl group is an unsubstitutedC₁₋₁₀ alkyl (e.g., —CH₃). In certain embodiments, the alkyl group is asubstituted C₁₋₁₀ alkyl.

“Perhaloalkyl” as defined herein refers to an alkyl group having from 1to 10 carbon atoms wherein all of the hydrogen atoms are eachindependently replaced halogen, e.g., selected from fluoro, bromo,chloro or iodo (“C₁₋₁₀ perhaloalkyl”). In some embodiments, the alkylmoiety has 1 to 8 carbon atoms (“C₁₋₈ perhaloalkyl”). In someembodiments, the alkyl moiety has 1 to 6 carbon atoms (“C₁₋₆perhaloalkyl”). In some embodiments, the alkyl moiety has 1 to 4 carbonatoms (“C₁₋₄ perhaloalkyl”). In some embodiments, the alkyl moiety has 1to 3 carbon atoms (“C₁₋₃ perhaloalkyl”). In some embodiments, the alkylmoiety has 1 to 2 carbon atoms (“C₁₋₂ perhaloalkyl”). In someembodiments, all of the hydrogen atoms are each replaced with fluoro. Insome embodiments, all of the hydrogen atoms are each replaced withchloro. Examples of perhaloalkyl groups include —CF₃, —CF₂CF₃,—CF₂CF₂CF₃, —CCl₃, —CFCl₂, —CF₂Cl and the like.

As used herein, alone or as part of another group, “alkenyl” refers to amonoradical of a straight-chain or branched hydrocarbon group havingfrom 2 to 10 carbon atoms and one or more carbon-carbon double bonds(“C₂₋₁₀ alkenyl”). In some embodiments, an alkenyl group has 2 to 9carbon atoms (“C₂₋₉ alkenyl”). In some embodiments, an alkenyl group has2 to 8 carbon atoms (“C₂₋₈ alkenyl”). In some embodiments, an alkenylgroup has 2 to 7 carbon atoms (“C₂₋₇ alkenyl”). In some embodiments, analkenyl group has 2 to 6 carbon atoms (“C₂₋₆ alkenyl”). In someembodiments, an alkenyl group has 2 to 5 carbon atoms (“C₂₋₅ alkenyl”).In some embodiments, an alkenyl group has 2 to 4 carbon atoms (“C₂₋₄alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms(“C₂₋₃ alkenyl”). In some embodiments, an alkenyl group has 2 carbonatoms (“C₂ alkenyl”). The one or more carbon-carbon double bonds can beinternal (such as in 2-butenyl) or terminal (such as in 1-butenyl).Examples of C₂₋₄ alkenyl groups include ethenyl (C₂), 1-propenyl (C₃),2-propenyl (C₃), 1-butenyl (C₄), 2-butenyl (C₄), butadienyl (C₄) and thelike. Examples of C₂₋₆ alkenyl groups include the aforementioned C₂₋₄alkenyl groups as well as pentenyl (C₅), pentadienyl (C₅), hexenyl (C₆)and the like. Additional examples of alkenyl include heptenyl (C₇),octenyl (C₈), octatrienyl (C₈) and the like. Unless otherwise specified,each instance of an alkenyl group is independently unsubstituted (an“unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with1, 2, 3, 4, or 5 substituents as described herein. In certainembodiments, the alkenyl group is an unsubstituted C₂₋₁₀ alkenyl. Incertain embodiments, the alkenyl group is a substituted C₂-10 alkenyl.

As used herein, alone or as part of another group, “alkynyl” refers to amonoradical of a straight-chain or branched hydrocarbon group havingfrom 2 to 10 carbon atoms and one or more carbon-carbon triple bonds(“C₂₋₁₀ alkynyl”). In some embodiments, an alkynyl group has 2 to 9carbon atoms (“C₂₋₉ alkynyl”). In some embodiments, an alkynyl group has2 to 8 carbon atoms (“C₂₋₈ alkynyl”). In some embodiments, an alkynylgroup has 2 to 7 carbon atoms (“C₂₋₇ alkynyl”). In some embodiments, analkynyl group has 2 to 6 carbon atoms (“C₂₋₆ alkynyl”). In someembodiments, an alkynyl group has 2 to 5 carbon atoms (“C₂₋₅ alkynyl”).In some embodiments, an alkynyl group has 2 to 4 carbon atoms (“C₂₋₄alkynyl”). In some embodiments, an alkynyl group has 2 to 3 carbon atoms(“C₂₋₃ alkynyl”). In some embodiments, an alkynyl group has 2 carbonatom (“C₂ alkynyl”). The one or more carbon-carbon triple bonds can beinternal (such as in 2-butynyl) or terminal (such as in 1-butynyl).Examples of C₂₋₄ alkynyl groups include, without limitation, ethynyl(C₂), 1-propynyl (C₃), 2-propynyl (C₃), 1-butynyl (C₄), 2-butynyl (C₄)and the like. Examples of C₂₋₆ alkenyl groups include the aforementionedC₂₋₄ alkynyl groups as well as pentynyl (C₅), hexynyl (C₆) and the like.Additional examples of alkynyl include heptynyl (C₇), octynyl (C₈) andthe like. Unless otherwise specified, each instance of an alkynyl groupis independently unsubstituted (an “unsubstituted alkynyl”) orsubstituted (a “substituted alkynyl”) with 1, 2, 3, 4, or 5 substituentsas described herein. In certain embodiments, the alkynyl group is anunsubstituted C₂₋₁₀ alkynyl. In certain embodiments, the alkynyl groupis a substituted C₂₋₁₀ alkynyl.

A “divalent C₁₋₆ hydrocarbon group” is a divalent C₁₋₆ alkyl group,divalent C₁₋₆ alkenyl group or divalent C₁ alkynyl group wherein one,two or three methylene units (—CH₂—) of the hydrocarbon chain areoptionally and independently replaced with one or more oxygen, sulfur ornitrogen atoms. In certain embodiments, the divalent C₁₋₆ hydrocarbongroup is a divalent C_(is) alkyl group. In certain embodiments, thedivalent C₁₋₆ hydrocarbon group is an unsubstituted divalent C₁₋₆hydrocarbon group (e.g., an unsubstituted divalent C₁ alkyl group).

As used herein, alone or as part of another group, “alkoxy” refers to analkyl group, as defined herein, substituted with an oxygen atom, whereinthe point of attachment is the oxygen atom. In certain embodiments, thealkyl group has 1 to 10 carbon atoms (“C₁₋₁₀ alkoxy”). In someembodiments, the alkyl group has 1 to 8 carbon atoms (“C₁₋₈ alkoxy”). Insome embodiments, the alkyl group has 1 to 6 carbon atoms (“C₁₋₆alkoxy”). In some embodiments, the alkyl group has 1 to 4 carbon atoms(“C₁₋₄ alkoxy”). Examples of C₁₋₄ alkoxy groups include methoxy (C₁),ethoxy (C₂), propoxy (C₃), isopropoxy (C₃), butoxy (C₄), tert-butoxy(C₅) and the like. Examples of C₁₋₆ alkoxy groups include theaforementioned C₁₋₄ alkoxy groups as well as pentyloxy (C₅),isopentyloxy (C₅), neopentyloxy (C₅), hexyloxy (C₆) and the like.Additional examples of alkoxy groups include heptyloxy (C₇), octyloxy(C₈) and the like. Unless otherwise specified, each instance of thealkyl moiety of the alkoxy group is independently unsubstituted (an“unsubstituted alkoxy”) or substituted (a “substituted alkoxy”) aresubstituted with 1, 2, 3, 4, or 5 substituents as described herein. Incertain embodiments, the alkoxy group is an unsubstituted C₂₋₁₀ alkoxy(e.g., —OCH₃). In certain embodiments, the alkoxy group is a substitutedC₂₋₁₀ alkoxy (e.g., perhaloalkoxy as defined herein).

“Perhaloalkoxy” refers to an alkoxy group wherein the all the hydrogenatoms of the alkyl moiety are each independently replaced with halogenatoms selected from fluoro, chloro, bromo and iodo. In certainembodiments, the alkyl moiety has 1 to 10 carbon atoms (“C₁₋₁₀perhaloalkoxy”). In some embodiments, the alkyl moiety has 1 to 8 carbonatoms (“C₁₋₈ perhaloalkoxy”). In some embodiments, the alkyl moiety has1 to 6 carbon atoms (“C₁₋₆ perhaloalkoxy”). In some embodiments, thealkyl moiety has 1 to 4 carbon atoms (“C₁₋₄ perhaloalkoxy”). In someembodiments, the alkyl moiety has 1 to 3 carbon atoms (“C₁₋₃perhaloalkoxy”). In some embodiments, the alkyl moiety has 1 to 2 carbonatoms (“C₁₋₂ perhaloalkoxy”). In some embodiments, all of the hydrogenatoms are each replaced with fluoro. In some embodiments, all of thehydrogen atoms are each replaced with chloro. Examples of perhaloalkoxygroups include, but are not limited to, —OCF₃, —OCF₂CF₃, —OCF₂CF₂CF₃,—OCCl₃, —OCFCl₂, —OCF₂Cl and the like.

As used herein, alone or as part of another group, “carbocyclyl” refersto a radical of a non-aromatic cyclic hydrocarbon group having from 3 to10 ring carbon atoms (“C₃₋₁₀ carbocyclyl”) and zero heteroatoms in thenon-aromatic ring system. In some embodiments, a carbocyclyl group has 3to 8 ring carbon atoms (“C₃₋₈ carbocyclyl”). In some embodiments, acarbocyclyl group has 3 to 6 ring carbon atoms (“C₃₋₆ carbocyclyl”). Insome embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms(“C₃₋₆ carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to10 ring carbon atoms (“C₅₋₁₀ carbocyclyl”). Examples of C₃₋₆ carbocyclylgroups include, without limitation, cyclopropyl (C₃), cyclobutyl (C₄),cyclopentyl (C₅), cyclopentenyl (C₅), cyclohexyl (C₆), cyclohexenyl(C₆), cyclohexadienyl (C₆) and the like. Examples of C₃₋₈ carbocyclylgroups include the aforementioned C₃₋₆ carbocyclyl groups as well ascycloheptyl (C₇), cycloheptadienyl (C₇), cycloheptatrienyl (C₇),cyclooctyl (C₈), bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, and thelike. Examples of C₃₋₁₀ carbocyclyl groups include the aforementionedC₃₋₈ carbocyclyl groups as well as octahydro-1H-indenyl,decahydronaphthalenyl, spiro[4.5]decanyl and the like. As the foregoingexamples illustrate, in certain embodiments, the carbocyclyl group iseither monocyclic (“monocyclic carbocyclyl”) or polycyclic (e.g.,containing a fused, bridged or spiraling system such as a bicyclicsystem (“bicyclic carbocyclyl”) or tricyclic system (“tricycliccarbocyclyl”)) and can be saturated or can contain one or morecarbon-carbon double or triple bonds. “Carbocyclyl” also includes ringsystems wherein the carbocyclyl ring, as defined above, is fused withone or more aryl or heteroaryl groups wherein the point of attachment ison the carbocyclyl ring. Unless otherwise specified, each instance of acarbocyclyl group is independently unsubstituted (an “unsubstitutedcarbocyclyl”) or substituted (a “substituted carbocyclyl”) with 1, 2, 3,4, or 5 substituents as described herein. In certain embodiments, thecarbocyclyl group is an unsubstituted C₃₋₁₀ carbocyclyl. In certainembodiments, the carbocyclyl group is a substituted C₃₋₁₀ carbocyclyl.

In some embodiments, “carbocyclyl” is a monocyclic, saturatedcarbocyclyl group having from 3 to 10 ring carbon atoms (“C₃₋₁₀cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ringcarbon atoms (“C₃₋₈ cycloalkyl”). In some embodiments, a cycloalkylgroup has 3 to 6 ring carbon atoms (“C₃₋₆ cycloalkyl”). In someembodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C₅₋₆cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ringcarbon atoms (“C₅₋₁₀ cycloalkyl”). Examples of C₅₋₆ cycloalkyl groupsinclude cyclopentyl (C₅) and cyclohexyl (C₅). Examples of C₃₋₆cycloalkyl groups include the aforementioned C₅₋₆ cycloalkyl groups aswell as cyclopropyl (C₃) and cyclobutyl (C₄). Examples of C₃₋₈cycloalkyl groups include the aforementioned C₃₋₆ cycloalkyl groups aswell as cycloheptyl (C₇) and cyclooctyl (C₈). Unless otherwisespecified, each instance of a cycloalkyl group is independentlyunsubstituted (an “unsubstituted cycloalkyl”) or substituted (a“substituted cycloalkyl”) with 1, 2, 3, 4, or 5 substituents asdescribed herein. In certain embodiments, the cycloalkyl group is anunsubstituted C₃₋₁₀ cycloalkyl. In certain embodiments, the cycloalkylgroup is a substituted C₃₋₁₀ cycloalkyl.

As used herein, alone or as part of another group, “heterocyclyl” refersto a radical of a 3- to 14-membered non-aromatic ring system having ringcarbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom isindependently selected from nitrogen, oxygen and sulfur (“3-14 memberedheterocyclyl”). In heterocyclyl groups that contain one or more nitrogenatoms, the point of attachment can be a carbon or nitrogen atom, asvalency permits. A heterocyclyl group can either be monocyclic(“monocyclic heterocyclyl”) or polycyclic (e.g., a fused, bridged orspiraling system such as a bicyclic system (“bicyclic heterocyclyl”) ortricyclic system (“tricyclic heterocyclyl”)), and can be saturated orcan contain one or more carbon-carbon double or triple bonds.Heterocyclyl polycyclic ring systems can include one or more heteroatomsin one or both rings. “Heterocyclyl” also includes ring systems whereinthe heterocycyl ring, as defined above, is fused with one or morecarbocycyl groups wherein the point of attachment is either on thecarbocycyl or heterocyclyl ring, or ring systems wherein theheterocyclyl ring, as defined above, is fused with one or more aryl orheteroaryl groups, wherein the point of attachment is on theheterocyclyl ring. In some embodiments, a heterocyclyl group is a 5-10membered non-aromatic ring system having ring carbon atoms and 1-4 ringheteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen and sulfur (“5-10 membered heterocyclyl”). In someembodiments, a heterocyclyl group is a 5-8 membered non-aromatic ringsystem having ring carbon atoms and 1-4 ring heteroatoms, wherein eachheteroatom is independently selected from nitrogen, oxygen and sulfur(“5-8 membered heterocyclyl”). In some embodiments, a heterocyclyl groupis a 5-6 membered non-aromatic ring system having ring carbon atoms and1-4 ring heteroatoms, wherein each heteroatom is independently selectedfrom nitrogen, oxygen and sulfur (“5-6 membered heterocyclyl”). In someembodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatomsselected from nitrogen, oxygen and sulfur. In some embodiments, the 5-6membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen,oxygen and sulfur. In some embodiments, the 5-6 membered heterocyclylhas 1 ring heteroatom selected from nitrogen, oxygen and sulfur.Exemplary 3-membered heterocyclyls containing 1 heteroatom include,without limitation, azirdinyl, oxiranyl, thiorenyl. Exemplary 4-memberedheterocyclyls containing 1 heteroatom include, without limitation,azetidinyl, oxetanyl and thietanyl. Exemplary 5-membered heterocyclylscontaining 1 heteroatom include, without limitation, tetrahydrofuranyl,dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl,dihydropyrrolyl and pyrrolyl-2,5-dione. Exemplary 5-memberedheterocyclyls containing 2 heteroatoms include, without limitation,dioxolanyl, oxathiolanyl and dithiolanyl. Exemplary 5-memberedheterocyclyls containing 3 heteroatoms include, without limitation,triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-memberedheterocyclyl groups containing 1 heteroatom include, without limitation,piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary6-membered heterocyclyl groups containing 2 heteroatoms include, withoutlimitation, piperazinyl, morpholinyl, dithianyl, dioxanyl. Exemplary6-membered heterocyclyl groups containing 2 heteroatoms include, withoutlimitation, triazinanyl. Exemplary 7-membered heterocyclyl groupscontaining 1 heteroatom include, without limitation, azepanyl, oxepanyland thiepanyl. Exemplary 8-membered heterocyclyl groups containing 1heteroatom include, without limitation, azocanyl, oxecanyl andthiocanyl. Exemplary bicyclic heterocyclyl groups include, withoutlimitation, indolinyl, isoindolinyl, dihydrobenzofuranyl,dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl,tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl,octahydroisochromenyl, decahydronaphthyridinyl, decahydro-1,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl,phthalimidyl, naphthalimidyl, chromanyl, chromenyl,1H-benzo[e][1,4]diazepinyl, 1,4,5,7-tetrahydropyrano[3,4-b]pyrrolyl,5,6-dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl,5,7-dihydro-4H-thieno[2,3-c]pyranyl,2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3-b]pyridinyl,4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridinyl,4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl,4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl,1,2,3,4-tetrahydro-1,6-naphthyridinyl, and the like. Unless otherwisespecified, each instance of heterocyclyl is independently unsubstituted(an “unsubstituted heterocyclyl”) or substituted (a “substitutedheterocyclyl”) with 1, 2, 3, 4, or 5 substituents as described herein.In certain embodiments, the heterocyclyl group is an unsubstituted 3-14membered heterocyclyl. In certain embodiments, the heterocyclyl group isa substituted 3-14 membered heterocyclyl.

As used herein, alone or as part of another group, “aryl” refers to aradical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic)aromatic ring system (e.g., having 6, 10 or 14 π electrons shared in acyclic array) having 6-14 ring carbon atoms and zero heteroatomsprovided in the aromatic ring system (“C₆₋₁₄ aryl”). In someembodiments, an aryl group has 6 ring carbon atoms (“C₆ aryl”; e.g.,phenyl). In some embodiments, an aryl group has 10 ring carbon atoms(“C₁₀ aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In someembodiments, an aryl group has 14 ring carbon atoms (“C₁₋₄ aryl”; e.g.,anthracyl). “Aryl” also includes ring systems wherein the aryl ring, asdefined above, is fused with one or more carbocyclyl or heterocyclylgroups wherein the radical or point of attachment is on the aryl ring.Unless otherwise specified, each instance of an aryl group isindependently unsubstituted (an “unsubstituted aryl”) or substituted (a“substituted aryl”) with 1, 2, 3, 4, or 5 substituents as describedherein. In certain embodiments, the aryl group is an unsubstituted C₆₋₁₄aryl. In certain embodiments, the aryl group is a substituted C₆₋₁₄aryl.

“Aralkyl” is a subset of “alkyl” and refers to an alkyl group, asdefined herein, substituted by an aryl group, as defined herein, whereinthe point of attachment is on the alkyl moiety.

As used herein, alone or as part of another group, “heteroaryl” refersto a radical of a 5-14 membered monocyclic or polycyclic (e.g., bicyclicor tricyclic) aromatic ring system (e.g., having 6, 10 or 14 π electronsshared in a cyclic array) having ring carbon atoms and 1-4 ringheteroatoms provided in the aromatic ring system, wherein eachheteroatom is independently selected from nitrogen, oxygen and sulfur(“5-14 membered heteroaryl”). In heteroaryl groups that contain one ormore nitrogen atoms, the point of attachment can be a carbon or nitrogenatom, as valency permits. Heteroaryl polycyclic ring systems can includeone or more heteroatoms in one or both rings. “Heteroaryl” also includesring systems wherein the heteroaryl ring, as defined above, is fusedwith one or more aryl groups wherein the point of attachment is eitheron the aryl or on the heteroaryl ring, or wherein the heteroaryl ring,as defined above, is fused with one or more carbocycyl or heterocycylgroups wherein the point of attachment is on the heteroaryl ring. Forpolycyclic heteroaryl groups wherein one ring does not contain aheteroatom (e.g., indolyl, quinolinyl, carbazolyl and the like) thepoint of attachment can be on either ring, i.e., either the ring bearinga heteroatom (e.g., 2-indolyl) or the ring that does not contain aheteroatom (e.g., 5-indolyl). In some embodiments, a heteroaryl group isa 5-10 membered aromatic ring system having ring carbon atoms and 1-4ring heteroatoms provided in the aromatic ring system, wherein eachheteroatom is independently selected from nitrogen, oxygen and sulfur(“5-10 membered heteroaryl”). In some embodiments, a heteroaryl group isa 5-8 membered aromatic ring system having ring carbon atoms and 1-4ring heteroatoms provided in the aromatic ring system, wherein eachheteroatom is independently selected from nitrogen, oxygen and sulfur(“5-8 membered heteroaryl”). In some embodiments, a heteroaryl group isa 5-6 membered aromatic ring system having ring carbon atoms and 1-4ring heteroatoms provided in the aromatic ring system, wherein eachheteroatom is independently selected from nitrogen, oxygen and sulfur(“5-6 membered heteroaryl”). In some embodiments, the 5-6 memberedheteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen andsulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ringheteroatoms selected from nitrogen, oxygen and sulfur. In someembodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selectedfrom nitrogen, oxygen and sulfur. Exemplary 5-membered heteroarylscontaining 1 heteroatom include, without limitation, pyrrolyl, furanyland thiophenyl. Exemplary 5-membered heteroaryls containing 2heteroatoms include, without limitation, imidazolyl, pyrazolyl,oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-memberedheteroaryls containing 3 heteroatoms include, without limitation,triazolyl, oxadiazolyl, thiadiazolyl. Exemplary 5-membered heteroarylscontaining 4 heteroatoms include, without limitation, tetrazolyl.Exemplary 6-membered heteroaryls containing 1 heteroatom include,without limitation, pyridinyl. Exemplary 6-membered heteroarylscontaining 2 heteroatoms include, without limitation, pyridazinyl,pyrimidinyl and pyrazinyl. Exemplary 6-membered heteroaryls containing 3or 4 heteroatoms include, without limitation, triazinyl and tetrazinyl,respectively. Exemplary 7 membered heteroaryls containing 1 heteroatominclude, without limitation, azepinyl, oxepinyl and thiepinyl. Exemplary5,6-bicyclic heteroaryls include, without limitation, indolyl,isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl,isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl,benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl,benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary6,6-bicyclic heteroaryls include, without limitation, naphthyridinyl,pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl,phthalazinyl and quinazolinyl. Exemplary tricyclic heteroaryls include,without limitation, phenanthridinyl, dibenzofuranyl, carbazolyl,acridinyl, phenothiazinyl, phenoxazinyl and phenazinyl. Unless otherwisespecified, each instance of a heteroaryl group is independentlyunsubstituted (an “unsubstituted heteroaryl”) or substituted (a“substituted heteroaryl”) with 1, 2, 3, 4, or 5 substituents asdescribed herein. In certain embodiments, the heteroaryl group is anunsubstituted 5-14 membered heteroaryl. In certain embodiments, theheteroaryl group is a substituted 5-14 membered heteroaryl.

“Heteroaralkyl” is a subset of “alkyl” and refers to an alkyl group, asdefined herein, substituted by a heteroaryl group, as defined herein,wherein the point of attachment is on the alkyl moiety.

As used herein, the term “partially unsaturated” refers to a ring moietythat includes at least one double or triple bond. The term “partiallyunsaturated” is intended to encompass rings having multiple sites ofunsaturation, but is not intended to include aromatic groups (e.g., arylor heteroaryl moieties) as herein defined.

Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroarylgroups, as defined herein, are optionally substituted (e.g.,“substituted” or “unsubstituted” alkyl, “substituted” or “unsubstituted”alkenyl, “substituted” or “unsubstituted” alkynyl, “substituted” or“unsubstituted” carbocyclyl, “substituted” or “unsubstituted”heterocyclyl, “substituted” or “unsubstituted” aryl or “substituted” or“unsubstituted” heteroaryl group). In general, the term “substituted”,whether preceded by the term “optionally” or not, means that at leastone hydrogen present on a group (e.g., a carbon or nitrogen atom etc.)is replaced with a permissible substituent, e.g., a substituent whichupon substitution results in a stable compound, e.g., a compound whichdoes not spontaneously undergo transformation such as by rearrangement,cyclization, elimination, or other reaction. Unless otherwise indicated,a “substituted” group has a substituent at one or more substitutablepositions of the group, and when more than one position in any givenstructure is substituted, the substituent is either the same ordifferent at each position.

Exemplary carbon atom substituents include, but are not limited to,halogen (i.e., fluoro (—F), bromo (—Br), chloro (—Cl), and iodo (—I)),—CN, —NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR^(aa), —ON(R^(bb))₂, —N(R^(bb))₂,—N(R^(bb))₃ ⁺X⁻, —N(OR^(cc))R^(bb), —SH, —SR^(aa), —SSR^(cc),—C(═O)R^(aa), —CO₂H, —CHO, —C(OR^(cc))₂, —CO₂R^(aa), —OC(═O)R^(aa),—OCO₂R^(aa), —C(═O)N(R^(bb))₂, —OC(═O)N(R^(bb))₂, —NR^(bb)C(═O)R^(aa),—NR^(bb)CO₂R^(aa), —NR^(bb)C(═O)N(R^(bb))₂, —C(═NR^(bb))R^(aa),—C(═NR^(bb))OR^(aa), —OC(═NR^(bb))R^(aa), —OC(═NR^(bb))OR^(aa),—C(═NR^(bb))N(R^(bb))₂, —OC(═NR^(bb))N(R^(bb))₂,—NR^(bb)C(═NR^(bb))N(R^(bb))₂, —C(═O)NR^(bb)SO₂R^(aa),—NR^(bb)SO₂R^(aa), —SO₂N(R^(bb))₂, —SO₂OR^(aa), —OSO₂R^(aa),—S(═O)R^(aa), —OS(═O)R^(aa), —OSi(R^(aa))₃—C(═S)N(R^(bb))₂,—C(═O)SR^(aa), —C(═S)SR^(aa), —SC(S)SR^(aa), —P(═O)₂R^(aa),—OP(═O)₂R^(aa), —P(═O)(R^(aa))₂, —OP(═O)(R^(bb))₂, —OP(═O)(OR^(cc))₂,—P(═O)₂N(R^(bb))₂, —OP(═O)₂N(R^(bb))₂, —P(═O)(NR^(bb))₂,—OP(═O)(NR^(bb))₂, —NR^(bb)P(═O)(OR^(cc))₂, —NR^(bb)P(═O)(NR^(bb))₂,—P(R^(cc))₂, —P(R^(cc))₃, —OP(R^(cc))₂, —OP(R^(cc))₃, —B(OR^(cc))₂,—BR^(aa)(OR^(cc)), C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, C₃₋₁₄ carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups;

or two geminal hydrogens on a carbon atom are replaced with the group═O, ═S, ═NN(R^(bb))₂, ═NNR^(bb)C(═O)R^(aa), ═NNR^(bb)C(═O)OR^(aa),═NNR^(bb)S(═O)₂R^(aa), ═NR^(bb), ═NOR^(cc);

each instance of R^(aa) is, independently, selected from C₁₋₁₀ alkyl,C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocyclyl,3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroaryl,wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl,and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5R^(dd) groups;

each instance of R^(bb) is, independently, selected from hydrogen, —OH,—N(R^(cc))₂, —CN, —C(═O)R^(aa), —C(═O)N(R^(cc))₂, —C(═NR^(cc))OR^(aa),—C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂, —SO₂R^(cc), —SO₂OR^(cc),—SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc), —C(═S)SR^(cc),—P(═O)₂R^(aa), —P(═O)(R^(aa))₂, —P(═O)₂N(R^(cc))₂, —P(═O)(NR^(cc))₂,C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 memberedheteroaryl, or two R^(cc) groups attached to an N atom are joined toform a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring,wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl,and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5R^(dd) groups;

each instance of R^(cc) is, independently, selected from hydrogen, C₁₋₁₀alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 memberedheteroaryl, or two R^(cc) groups attached to an N atom are joined toform a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring,wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl,and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5R^(dd) groups;

each instance of R^(dd) is, independently, selected from halogen, —CN,—NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR^(ee), —ON(R^(ff))₂, —N(R^(ff))₂,—N(R^(ff))₃ ⁺X—, —N(OR^(ee))R^(ff), —SH, —SR^(ee), —SSR^(ee),—C(═O)R^(ee), —CO₂H, —CO₂R^(ee), —OC(═O)R^(ee), —OCO₂R^(ee),—C(═O)N(R)₂, —OC(═O)N(R)₂, —NR^(ff)C(═O)R^(ee), —NeCO₂R^(ee),—NR^(ff)C(═O)N(R^(ff))₂, —C(═NR^(ff))OR^(ee), —OC(═NR^(ff))R^(ee),—OC(═NR^(ff))OR^(ee), —C(═NR^(ff))N(R^(ff))₂, —OC(═NR^(ff))N(R^(ff))₂,—NR^(ff)C(═NR^(ff))N(R^(ff))₂, —NR^(ff)SO₂R^(ee), —SO₂N(R^(ff))₂,—SO₂R^(ee), —SO₂OR^(ee), —OSO₂R^(ee), —S(═O)R^(ee), —Si(R^(ee))₃,—OSi(R^(ee))₃, —C(═S)N(R^(ff))₂, —C(═O)SR^(ee), —C(═S)SR^(ee),—SC(═S)SR^(ee), —P(═O)₂R^(ee), —P(═O)(R^(ee))₂, —OP(═O)(R^(ee))₂,—OP(═O)(OR^(ee))₂, C₁₋₆ alkyl, C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ carbocyclyl, 3-10 membered heterocyclyl, C₆₋₁₀ aryl, 5-10membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl,heterocyclyl, aryl, and heteroaryl is independently substituted with 0,1, 2, 3, 4, or 5 R^(gg) groups, or two geminal R^(dd) substituents canbe joined to form ═O or ═S;

each instance of R^(ee) is, independently, selected from C₁₋₆ alkyl,C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl, C₆₋₁₀aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, whereineach alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^(gg)groups;

each instance of R^(ff) is, independently, selected from hydrogen, C₁₋₆alkyl, C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl,3-10 membered heterocyclyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl, ortwo R^(if) groups attached to an N atom are joined to form a 3-14membered heterocyclyl or 5-14 membered heteroaryl ring, wherein eachalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroarylis independently substituted with 0, 1, 2, 3, 4, or 5 R^(gg) groups; and

each instance of R^(gg) is, independently, halogen, —CN, —NO₂, —N₃,—SO₂H, —SO₃H, —OH, —OC₁₋₆ alkyl, —ON(C₁₋₆ alkyl)₂, —N(C₁₋₆ alkyl)₂,—N(C₁₋₆ alkyl)₃X, —NH(C₁₋₆ alkyl)₂X, —NH₂(C₁₋₆ alkyl)X, —NH₃X, —N(OC₁₋₆alkyl)(C₁₋₆ alkyl), —N(OH)(C₁₋₆ alkyl), —NH(OH), —SH, —SC₁₋₆ alkyl,—SS(C₁₋₆ alkyl), —C(═O)(C₁₋₆ alkyl), —CO₂H, —OC₂(C₁₋₆ alkyl),—OC(═O)(C₁₋₆ alkyl), —OCO₂(C₁₋₆ alkyl), —C(═O)NH₂, —C(═O)N(C₁₋₆ alkyl)₂,—OC(═O)NH(C₁₋₆ alkyl), —NHC(═O)(C₁₋₆ alkyl), —N(C₁₋₆ alkyl)C(═O)(C₁₋₆alkyl), —NHCO₂(C₁₋₆ alkyl), —NHC(═O)N(C₁₋₆ alkyl)₂, —NHC(═O)NH(C₁₋₆alkyl), —NHC(═O)NH₂, —C(═NH)O(C₁₋₆ alkyl), —OC(═NH)(C₁₋₆ alkyl),—OC(═NH)OC₁₋₆ alkyl, —C(═NH)N(C₁₋₆ alkyl)₂, —C(═NH)NH(C₁₋₆ alkyl),—C(═NH)NH₂, —OC(═NH)N(C₁₋₆ alkyl)₂, —OC(NH)NH(C₁₋₆ alkyl), —OC(NH)NH₂,—NHC(NH)N(C₁₋₆ alkyl)₂, —NHC(═NH)NH₂, —NHSO₂ (C₁₋₆ alkyl), —SO₂N(C₁₋₆alkyl)₂, —SO₂NH(C₁₋₆ alkyl), —SO₂NH₂, —SO₂C₁₋₆ alkyl, —SO₂OC₁₋₆ alkyl,—OSO₂C₁₋₆ alkyl, —SOC₁₋₆ alkyl, —Si(C₁₋₆ alkyl)₃, —OSi(C_(is) alkyl)₃—C(═S)N(C₁₋₆ alkyl)₂, C(═S)NH(C₁₋₆ alkyl), C(═S)NH₂, —C(═O)S(C₁₋₆alkyl), —C(═S)SC₁₋₆ alkyl, —SC(═S)SC₁₋₆ alkyl, —P(═O)₂(C₁₋₆ alkyl),—P(═O)(C₁₋₆ alkyl)₂, —OP(═O)(C₁₋₆ alkyl)₂, —OP(═O)(OC₁₋₆ alkyl)₂, C₁alkyl, C₁ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl-C₃₋₁₀ carbocyclyl,C₆₋₁₀ aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; or twogeminal R^(gg) substituents can be joined to form ═O or ═S;

wherein X⁻ is a counterion.

As used herein, a “counterion” is a negatively charged group associatedwith a positively charged quarternary amine in order to maintainelectronic neutrality. Exemplary counterions include halide ions (e.g.,F⁻, Cl⁻, Br⁻, I⁻), NO₃ ⁻, ClO₄ ⁻, OH⁻, H₂PO₄ ⁻, HSO₄ ⁻, sulfonate ions(e.g., methansulfonate, trifluoromethanesulfonate, p-toluenesulfonate,benzenesulfonate, 10-camphor sulfonate, naphthalene-2-sulfonate,naphthalene-1-sulfonic acid-5-sulfonate, ethan-1-sulfonicacid-2-sulfonate, and the like) and carboxylate ions (e.g., acetate,ethanoate, propanoate, benzoate, glycerate, lactate, tartrate,glycolate, and the like).

Nitrogen atoms can be substituted or unsubstituted as valency permits,and include primary, secondary, tertiary and quarternary nitrogen atoms.Exemplary nitrogen atom substitutents include, but are not limited to,hydrogen, —OH, —OR^(aa), —N(R^(cc))₂, —CN, —C(═O)R^(aa),—C(═O)N(R^(cc))₂, —CO₂R^(cc), —SO₂R^(cc), —C(═NR^(bb))R^(aa),—C(═NR^(cc))OR^(aa), —C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂, —SO₂R^(cc),—SO₂OR^(cc), —SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc), —C(═S)SR^(cc),—P(═O)₂R^(aa), —P(═O)(R^(aa))₂, —P(═O)₂N(R^(cc))₂, —P(═O)(NR^(cc))₂,C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 memberedheteroaryl, or two R^(cc) groups attached to an N atom are joined toform a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring,wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl,and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5R^(dd) groups, and wherein R^(aa), R^(bb), R^(cc) and R^(dd) are asdefined above.

In certain embodiments, the substituent present on the nitrogen atom isan amino protecting group. Amino protecting groups include, but are notlimited to, —OH, —OR^(aa), —N(R^(cc))₂, —C(═O)R^(aa), —C(═O)N(R^(cc))₂,—CO₂R^(aa), —SO₂R^(aa), —C(═NR^(cc))R^(aa), —C(═NR^(cc))OR^(aa),—C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂, —SO₂R^(aa), —SO₂OR^(cc),—SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc), —C(═S)SR^(cc), C₁₋₁₀ alkyl(e.g., aralkyl groups), C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocyclyl,3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroarylgroups, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl,aralkyl, aryl, and heteroaryl is independently substituted with 0, 1, 2,3, 4, or 5 R^(dd) groups, and wherein R^(aa), R^(bb), R^(cc) and R^(dd)are as defined above. Amino protecting groups are well known in the artand include those described in detail in Protecting Groups in OrganicSynthesis, T. W. Greene and P. G. M. Wuts, 3^(rd) edition, John Wiley &Sons, 1999, incorporated herein by reference.

For example, amino protecting groups such as amide groups (e.g.,—C(═O)R^(aa)) include, but are not limited to, formamide, acetamide,chloroacetamide, trichloroacetamide, trifluoroacetamide,phenylacetamide, 3-phenylpropanamide, picolinamide,3-pyridylcarboxamide, N-benzoylphenylalanyl derivative, benzamide,p-phenylbenzamide, o-nitophenylacetamide, o-nitrophenoxyacetamide,acetoacetamide, (N′-dithiobenzyloxycarbonylamino)acetamide,3-(p-hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide,2-methyl-2-(o-nitrophenoxy)propanamide,2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide,3-methyl-3-nitrobutanamide, o-nitro cinnamide, N-acetylmethioninederivative, o-nitrobenzamide and o-(benzoyloxymethyl)benzamide.

Amino protecting groups such as carbamate groups (e.g., —C(═O)OR^(aa))include, but are not limited to, methyl carbamate, ethyl carbamante,9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethylcarbamate, 9-(2,7-dibromo)fluoroenylmethyl carbamate,2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methylcarbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc),2,2,2-trichloro ethyl carbamate (Troc), 2-trimethylsilylethyl carbamate(Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1-methylethylcarbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate,1,1-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC),1,1-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC),1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc),1-(3,5-di-t-butylphenyl)-1-methylethyl carbamate (t-Bumeoc), 2-(2′- and4′-pyridyl)ethyl carbamate (Pyoc), 24N,N-dicyclohexylcarboxamido)ethylcarbamate, t-butyl carbamate (BOC), 1-adamantyl carbamate (Adoc), vinylcarbamate (Voc), allyl carbamate (Alloc), 1-isopropylallyl carbamate(Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc),8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithiocarbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz),p-nitrobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzylcarbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzylcarbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate,2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate,2-(p-toluene sulfonyl)ethyl carbamate, [2-(1,3-dithianyl)]methylcarbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc),2,4-dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate(Peoc), 2-triphenylphosphonioisopropyl carbamate (Ppoc),1,1-dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate,p-(dihydroxyboryl)benzyl carbamate, 5-benzisoxazolylmethyl carbamate,2-(trifluoromethyl)-6-chromonylmethyl carbamate (Tcroc), m-nitrophenylcarbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate,3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl(o-nitrophenyl)methylcarbamate, t-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzylcarbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentylcarbamate, cyclopropylmethyl carbamate, p-decyloxybenzyl carbamate,2,2-dimethoxycarbonylvinyl carbamate, o-(N,N-dimethylcarboxamido)benzylcarbamate, 1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl carbamate,1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate,2-furanylmethyl carbamate, 2-iodoethyl carbamate, isoborynl carbamate,isobutyl carbamate, isonicotinyl carbamate,p-(p′-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate,1-methylcyclohexyl carbamate, 1-methyl-1-cyclopropylmethyl carbamate,1-methyl-1-(3,5-dimethoxyphenyl)ethyl carbamate,1-methyl-1-(p-phenylazophenyl)ethyl carbamate, 1-methyl-1-phenylethylcarbamate, 1-methyl-1-(4-pyridyl)ethyl carbamate, phenyl carbamate,p-(phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate,4-(trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzylcarbamate.

Amino protecting groups such as sulfonamide groups (e.g., —S(═O)₂R^(aa))include, but are not limited to, p-toluenesulfonamide (Ts),benzenesulfonamide, 2,3,6,-trimethyl-4-methoxybenzenesulfonamide (Mtr),2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide(Mte), 4-methoxybenzenesulfonamide (Mbs),2,4,6-trimethylbenzenesulfonamide (Mts),2,6-dimethoxy-4-methylbenzenesulfonamide (iMds),2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide(Ms), β-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide,4-(4′,8′-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS),benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

Other amino protecting groups include, but are not limited to,phenothiazinyl-(10)-carbonyl derivative, N′-p-toluenesulfonylaminocarbonyl derivative, N′-phenylaminothiocarbonyl derivative,N-benzoylphenylalanyl derivative, N-acetylmethionine derivative,4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts),N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole,N-1,1,4,4-tetramethyldisilylazacyclopentane adduct (STABASE),5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 1-substituted3,5-dinitro-4-pyridone, N-methylamine, N-allylamine,N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine,N-(1-isopropyl-4-nitro-2-oxo-3-pyroolin-3-yl)amine, quaternary ammoniumsalts, N-benzylamine, N-di(4-methoxyphenyl)methylamine,N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr),N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr),N-9-phenylfluorenylamine (PhF),N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm),N-2-picolylamino N′-oxide, N-1,1-dimethylthiomethyleneamine,N-benzylideneamine, N-p-methoxybenzylideneamine, N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine,N—(N′,N′-dimethylaminomethylene)amine, N,N′-isopropylidenediamine,N-p-nitrobenzylideneamine, N-salicylideneamine,N-5-chlorosalicylideneamine,N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine,N-cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)amine,N-borane derivative, N-diphenylborinic acid derivative,N-[phenyl(pentacarbonylchromium- or tungsten)carbonyl]amine, N-copperchelate, N-zinc chelate, N-nitroamine, N-nitrosoamine, amine N-oxide,diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt),diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzylphosphoramidate, diphenyl phosphoramidate, benzenesulfenamide,o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide,pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide,triphenylmethylsulfenamide and 3-nitropyridine sulfenamide (Npys).

As used herein, a “leaving group” is an art-understood term referring toa molecular fragment that departs with a pair of electrons inheterolytic bond cleavage, wherein the molecular fragment is an anion orneutral molecule. See, for example, Smith, March Advanced OrganicChemistry 6th ed. (501-502).

These and other exemplary substituents are described in more detail inthe Detailed Description, the Exemplification and in the claims. Theinvention is not intended to be limited in any manner by the aboveexemplary listing of substituents.

As used herein, a “pharmaceutically acceptable form thereof” includespharmaceutically acceptable salts, hydrates, solvates, prodrugs,tautomers, isomers, and/or polymorphs of a compound of the presentinvention, as defined below and herein.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, S. M. Berge etal., describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977, 66, 1-19. Pharmaceutically acceptablesalts of the compounds of this invention include those derived fromsuitable inorganic and organic acids and bases. Examples ofpharmaceutically acceptable, nontoxic acid addition salts are salts ofan amino group formed with inorganic acids such as hydrochloric acid,hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid orwith organic acids such as acetic acid, oxalic acid, maleic acid,tartaric acid, citric acid, succinic acid or malonic acid or by usingother methods used in the art such as ion exchange. Otherpharmaceutically acceptable salts include adipate, alginate, ascorbate,aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate,camphorate, camphorsulfonate, citrate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate,glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate,hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate,lactate, laurate, lauryl sulfate, malate, maleate, malonate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate,oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate,phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate,tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts,and the like. Salts derived from appropriate bases include alkali metal,alkaline earth metal, ammonium and N⁺(C₁₋₄-alkyl)₄ salts. Representativealkali or alkaline earth metal salts include sodium, lithium, potassium,calcium, magnesium, and the like. Further pharmaceutically acceptablesalts include, when appropriate, nontoxic ammonium, quaternary ammonium,and amine cations formed using counterions such as halide, hydroxide,carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and arylsulfonate.

In certain embodiments, the pharmaceutically acceptable form thereof isan isomer. As used herein, the term “isomer” includes any and allgeometric isomers and stereoisomers. For example, “isomers” include cis-and trans-isomers, E- and Z-isomers, R- and S-enantiomers,diastereomers, (D)-isomers, (L)-isomers, racemic mixtures thereof, andother mixtures thereof, as falling within the scope of the invention.

In certain embodiments, the pharmaceutically acceptable form thereof isa tautomer. As used herein, the term “tautomer” includes two or moreinterconvertable compounds resulting from at least one formal migrationof a hydrogen atom and at least one change in valency (e.g., a singlebond to a double bond, a triple bond to a single bond, or vice versa).The exact ratio of the tautomers depends on several factors, includingtemperature, solvent, and pH. Tautomerizations (i.e., the reactionproviding a tautomeric pair) may catalyzed by acid or base. Exemplarytautomerizations include keto-to-enol; amide-to-imide; lactam-to-lactim;enamine-to-imine; and enamine-to-(a different) enamine tautomerizations.

In certain embodiments, the pharmaceutically acceptable form thereof isa hydrate or solvate. As used herein, the term “hydrate” refers to acompound non-covalently associated with one or more molecules of water.Likewise, “solvate” refers to a compound non-covalently associated withone or more molecules of an organic solvent.

In certain embodiments, the pharmaceutically acceptable form thereof isa prodrug. As used herein, the term “prodrug” refers to a derivative ofa parent compound that requires transformation within the body in orderto release the parent compound. In certain cases, a prodrug has improvedphysical and/or delivery properties over the parent compound. Prodrugsare typically designed to enhance pharmaceutically and/orpharmacokinetically based properties associated with the parentcompound. The advantage of a prodrug can lie in its physical properties,such as enhanced water solubility for parenteral administration atphysiological pH compared to the parent compound, or it enhancesabsorption from the digestive tract, or it may enhance drug stabilityfor long-term storage.

In certain embodiments, the pharmaceutically acceptable form thereof isa polymorph. As used herein, “polymorph” refers to a compound havingmore than one crystal structure, e.g., resulting from differences inmolecular packing and/or molecular conformation of the compound in thesolid state.

SEQUENCE IDENTIFICATION NUMBERS

SEQ. ID. NO.: Homo sapiens FAAH amino acid sequence:MVQYELWAALPGASGVALACCFVAAAVALRWSGRRTARGAVVRARQRQRAGLENMDRAAQRFRLQNPDLDSEALLALPLPQLVQKLHSRELAPEAVLFTYVGKAWEVNKGTNCVTSYLADCETQLSQAPRQGLLYGVPVSLKECFTYKGQDSTLGLSLNEGVPAECDSVVVHVLKLQGAVPFVHTNVPQSMFSYDCSNPLFGQTVNPWKSSKSPGGSSGGEGALIGSGGSPLGLGTDIGGSIRFPSSFCGICGLKPTGNRLSKSGLKGCVYGQEAVRLSVGPMARDVESLALCLRALLCEDMFRLDPTVPPLPFREEVYTSSQPLRVGYYETDNYTMPSPAMRRAVLETKQSLEAAGHTLVPFLPSNIPHALETLSTGGLFSDGGHTFLQNFKGDFVDPCLGDLVSILKLPQWLKGLLAFLVKPLLPRLSAFLSNMKSRSAGKLWELQHEIEVYRKTVIAQWRALDLDVVLTPMLAPALDLNAPGRATGAVSYTMLYNCLDFPAGVVPVTTVTAEDEAQMEHYRGYFGDIWDKMLQKGMKKSVGLPVAVQCVALPWQEELCLRFMREVERLMTPEKQSS

DETAILED DESCRIPTION I. Compounds

The present invention provides isoxazoline FAAH inhibitor compounds ofthe formula (I):

or a pharmaceutically acceptable form thereof,

wherein:

each of R^(a), R^(b), and R^(c) independently is selected from —H, C₁₋₁₀alkyl and C₁₋₁₀ perhaloalkyl, R^(d) is the group -L-Z, and Z is selectedfrom 3-14 membered heterocyclyl and 5-14 membered heteroaryl;

L is a covalent bond or a divalent C₁₋₆ hydrocarbon group, wherein one,two or three methylene units of L are optionally and independentlyreplaced with one or more oxygen, sulfur or nitrogen atoms;

G is selected from —CN, —NO₂, —S(═O)R^(e), —SO₂R^(e), —SO₂NR^(f)R^(e),—PO₂R^(e), —PO₂OR^(e), —PO₂NR^(f)R^(e), —(C═O)R^(e), —(C═O)OR^(e),—(C═O)NR^(f)R^(e), —Br, —I, —F, —Cl, —OR^(e), —ONR^(f)R^(e),—ONR^(f)(C═O)R^(e), —ONR^(f)SO₂R^(e), —ONR^(f)PO₂R^(e),—ONR^(f)PO₂OR^(e), —SR^(e), —OSO₂R^(e), —NR^(f)SO₂R^(e), —OPO₂R^(e),—OPO₂OR^(e), —NR^(f)PO₂R^(e), —NR^(f)PO₂OR^(e), —OPO₂NR^(f)R^(e),—O(C═O)R^(e), —O(C═O)OR^(e), —NR^(f)R^(e), —NR^(f)(C═O)R^(e),—NR^(f)(C═O)OR^(e), —O(C═O)NR^(f)R^(e), —NR^(f)(C═NR^(f))NR^(f)R^(e),—O(C═NR^(f))NR^(f)R^(e), —NR^(f)(C═NR^(f))OR^(e), —[N(R^(f))₂R^(e)]⁺X⁻wherein X⁻ is a counterion; and

each R^(e) is selected from C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl,C₃₋₁₀ carbocycyl, C₆₋₁₄ aryl, 3-14 membered heterocyclyl and 5-14membered heteroaryl; each R^(f) attached to a nitrogen atom is,independently, selected from —H, C₁₋₁₀ alkyl, or an amino protectinggroup; or R^(e) and R^(f) are joined to form an 3-14 memberedheterocyclyl ring or an 5-14 membered heteroaryl ring.

Group G

As defined above, G is selected from —CN, —NO₂, —S(═O)R^(e), —SO₂R^(e),—SO₂NR^(f)R^(e), —PO₂R^(e), —PO₂OR^(e), —PO₂NR^(f)R^(e), —(C═O)R^(e),—(C═O)OR^(e), —(C═O)NR^(f)R^(e), —Br, —I, —F, —Cl, —OR^(e),—ONR^(f)R^(e), —ONR^(f)(C═O)R^(e), —ONR^(f)SO₂R^(e), —ONR^(f)PO₂R^(e),—ONR^(f)PO₂OR^(e), —SR^(e), —OSO₂R^(e), —NR^(f)SO₂R^(e), —OPO₂R^(e),—OPO₂OR^(e), —NR^(f)PO₂R^(e), —NR^(f)PO₂OR^(e), —OPO₂NR^(f)R^(e),—O(C═O)R^(e), —O(C═O)OR^(e), —NR^(f)R^(e), —NR^(f)(C═O)R^(e),—NR^(f)(C═O)OR^(e), —O(C═O)NR^(f)R^(e), —NR^(f)(C═NR^(f))NR^(f)R^(e),—O(C═NR^(f))NR^(f)R^(e), —NR^(f)(C═NR^(f))OR^(e), —[N(R^(f))₂R^(e)]⁺X⁻wherein X⁻ is a counterion;

and wherein R^(e) is selected from C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, C₃₋₁₀ carbocycyl, C₆₋₁₄ aryl, 3-14 membered heterocyclyl and5-14 membered heteroaryl; each R^(f) attached to a nitrogen atom is,independently, selected from —H, C₁₋₁₀ alkyl, or an amino protectinggroup; or R^(e) and R^(f) are joined to form an 3-14 memberedheterocyclyl ring or an 5-14 membered heteroaryl ring.

In certain embodiments, G is not a leaving group, e.g., for example, Gis selected from —F, —CN, —NO₂, —S(═O)R^(e), —SO₂R^(e), —SO₂NR^(f)R^(e),—PO₂R^(e), —PO₂OR^(e), —PO₂NR^(f)R^(e), —(C═O)R^(e), —(C═O)OR^(e), and—(C═O)NR^(f)R^(e).

In certain embodiments, G is selected from —CN and —NO₂. In certainembodiments, G is —CN. In certain embodiments, G is —NO₂.

In certain embodiments, G is selected from —S(═O)R^(e), —SO₂R^(e), and—SO₂NR^(f)R^(e). In certain embodiments, G is —S(═O)R^(e). In certainembodiments, G is —SO₂R^(e). In certain embodiments, G is—SO₂NR^(f)R^(e).

In certain embodiments, G is selected from —PO₂R^(e), —PO₂OR^(e) and—PO₂NR^(f)R^(e). In certain embodiments, G is —PO₂R^(e). In certainembodiments, G is —PO₂OR^(e). In certain embodiments, G is—PO₂NR^(f)R^(e).

In certain embodiments, G is selected from —(C═O)R^(e), —(C═O)OR^(e) and—(C═O)NR^(f)R^(e). In certain embodiments, G is —(C═O)R^(e). In certainembodiments, G is —(C═O)OR^(e). In certain embodiments, G is—(C═O)NR^(f)R^(e).

However, in certain embodiments, G is a leaving group, e.g., forexample, G is selected from —Cl, —Br, —I, —OR^(e), —ONR^(f)R^(e),—ONR^(f)(C═O)R^(e), —ONR^(f)SO₂R^(e), —ONR^(f)PO₂R^(e),—ONR^(f)PO₂OR^(e), —SR^(e), —OSO₂R^(e), —NR^(f)SO₂R^(e), —OPO₂R^(e),—OPO₂OR^(e), —NR^(f)PO₂R^(e), —NR^(f)PO₂OR^(e), —OPO₂NR^(f)R^(e),—O(C═O)R^(e), —O(C═O)OR^(e), —NR^(f)R^(e), —NR^(f)(C═O)R^(e),—NR^(f)(C═O)OR^(e), —O(C═O)NR^(f)R^(e), —NR^(f)(C═NR^(f))NR^(f)R^(e),—O(C═NR^(f))NR^(f)R^(e), —NR^(f)(C═NR^(f))OR^(e), and —[N(R^(f))₂R^(e)]wherein X⁻ is a counterion.

In certain embodiments, G is a halogen; i.e., selected from —F, —Cl, —Brand —I. In certain embodiments, G is —F. In certain embodiments, G is—Br. In certain embodiments, G is —I. In certain embodiments, G is —Cl.However, in certain embodiments, G is not a halogen. For example, incertain embodiments, G is not —Br. In certain embodiments, G is not —I.In certain embodiments, G is not —F. In certain embodiments, G is not—Cl.

In certain embodiments, G is selected from −OR^(e), —ONR^(f)R^(e),—ONR^(f)(C═O)R^(e), —ONR^(f)SO₂R^(e), —ONR^(f)PO₂R^(e),—ONR^(f)PO₂OR^(e), —OSO₂R^(e), —OPO₂R^(e), —OPO₂OR^(e),—OPO₂NR^(f)R^(e), —O(C═O)R^(e), —O(C═O)OR^(e), —O(C═O)NR^(f)R^(e) and—O(C═NR^(f))NR^(f)R^(e). In certain embodiments, G is selected from—OR^(e), —O(C═O)R^(e), —O(C═O)OR^(e), —O(C═O)NR^(f)R^(e) and—O(C═NR^(f))NR^(f)R^(e). In certain embodiments, G is selected from—ONR^(f)R^(e), —ONR^(f)(C═O)R^(e), —ONR^(f)SO₂R^(e), —ONR^(f)PO₂R^(e),—ONR^(f)PO₂OR^(e), —OPO₂NR^(f)R^(e), —O(C═O)NR^(f)R^(e) and—O(C═NR^(f))NR^(f)R^(e). In certain embodiments, G is —OR^(e). Incertain embodiments, G is —ONR^(f)R^(e). In certain embodiments, G is—ONR^(f)(C═O)R^(e). In certain embodiments, G is —ONR^(f)SO₂R^(e). Incertain embodiments, G is —ONR^(f)PO₂R^(e). In certain embodiments, G is—ONR^(f)PO₂OR^(e). In certain embodiments, G is —OSO₂R^(e). In certainembodiments, G is —OPO₂R^(e). In certain embodiments, G is —OPO₂OR^(e).In certain embodiments, G is —OPO₂NR^(f)R^(e). In certain embodiments, Gis —O(C═O)R^(e). In certain embodiments, G is —O(C═O)OR^(e). In certainembodiments, G is —O(C═O)NR^(f)R^(e). In certain embodiments, G is—O(C═NR^(f))NR^(f)R^(e).

In certain embodiments, G is selected from —OR^(e) and —SR^(e). Incertain embodiments, G is selected from —OR^(e). In certain embodiments,G is —SR^(e).

In certain embodiments, G is selected from —NR^(f)SO₂R^(e),—NR^(f)PO₂R^(e), —NR^(f)PO₂OR^(e), —NR^(f)R^(e), —NR^(f)(C═O)R^(e),—NR^(f)(C═O)OR^(e), —NR^(f)(C═NR^(f))NR^(f)R^(e),—NR^(f)(C═NR^(f))OR^(e) and —[N(R^(f))₂R^(e)]⁺X⁻ wherein X⁻ is acounterion. In certain embodiments, G is selected from —NR^(f)SO₂R^(e),—NR^(f)PO₂R^(e), —NR^(f)PO₂OR^(e), —NR^(f)R^(e), —NR^(f)(C═O)R^(e) and—NR^(f)(C═O)OR^(e). In certain embodiments, G is selected from—NR^(f)SO₂R^(e), —NR^(f)R^(e), —NR^(f)(C═O)R^(e) and —NR^(f)(C═O)OR^(e).In certain embodiments, G is —NR^(f)SO₂R^(e). In certain embodiments, Gis —NR^(f)PO₂R^(e). In certain embodiments, G is —NR^(f)PO₂OR^(e). Incertain embodiments, G is —NR^(f)R^(e). In certain embodiments, G is—NR^(f)(C═O)R^(e). In certain embodiments, G is —NR^(f)(C═O)OR^(e). Incertain embodiments, G is —NR^(f)(C═NR^(f))NR^(f)R^(e). In certainembodiments, G is —NR^(f)(C═NR^(f))OR^(e). In certain embodiments, G is—[N(R^(f))₂R^(e)]⁺X⁻ wherein X⁻ is a counterion.

Additional embodiments of G, included in the description of groups R^(e)and R^(f), and further exemplified in the Tables and Examples, isprovided below and herein.

R^(e) of Group G

As defined generally above, in certain embodiments, wherein G isselected from —S(═O)R^(e), —SO₂R^(e), —SO₂NR^(f)R^(e), —PO₂R^(e),—PO₂OR^(e), —PO₂NR^(f)R^(e), —(C═O)R^(e), —(C═O)OR^(e),—(C═O)NR^(f)R^(e), —OR^(e), —ONR^(f)R^(e), —ONR^(f)(C═O)R^(e),—ONR^(f)SO₂R^(e), —ONR^(f)PO₂R^(e), —ONR^(f)PO₂OR^(e), —SR^(e),—OSO₂R^(e), —NR^(f)SO₂R^(e), —OPO₂R^(e), —OPO₂OR^(e), —NR^(f)PO₂R^(e),—NR^(f)PO₂OR^(e), —OPO₂NR^(f)R^(e), —O(C═O)R^(e), —O(C═O)OR^(e),—NR^(f)R^(e), —NR^(f)(C═O)R^(e), —NR^(f)(C═O)OR^(e), —O(C═O)NR^(f)R^(e),—NR^(f)(C═NR^(f))NR^(f)R^(e), —O(C═NR^(f))NR^(f)R^(e),—NR^(f)(C═NR^(f))OR^(e), and —[N(R^(f))₂R^(e)]⁺X⁻ wherein X⁻ is acounterion, R^(e) is selected from C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, C₃₋₁₀ carbocycyl, C₆₋₁₄ aryl, 3-14 membered heterocyclyl and5-14 membered heteroaryl.

In certain embodiments, R^(e) is selected from C₁₋₁₀ alkyl, C₂₋₁₀alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocycyl, C₆₋₁₄ aryl, 3-14 memberedheterocyclyl and 5-14 membered heteroaryl, wherein the alkyl, alkenyl,alkynyl, carbocycyl, aryl, heterocyclyl, and heteroaryl groups aresubstituted with 0, 1, 2, 3, 4 or 5 R^(h) groups, as defined below andherein.

In certain embodiments, R^(e) is C₁₋₁₀ alkyl. In certain embodiments,R^(e) is C₁₋₆ alkyl. In certain embodiments, R^(e) is C₁₋₆ alkylsubstituted with 0, 1, 2, 3, 4 or 5 R^(h) groups. In certainembodiments, R^(e) is a C₁₋₅ alkyl substituted with 0, 1, 2, 3, 4 or 5R^(h) groups. In certain embodiments, R^(e) is a C₁₋₄ alkyl substitutedwith 0, 1, 2, 3 or 4 R^(h) groups. In certain embodiments, R^(e) is aC₁₋₃ alkyl substituted with 0, 1, 2 or 3 R^(h) groups. In certainembodiments, R^(e) is a C₁₋₂ alkyl substituted with 0, 1 or 2 R^(h)groups. Exemplary alkyl groups include, but are not limited to, methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,pentyl, isopentyl, neopentyl, and hexyl, wherein such groups aresubstituted with 0, 1, 2, 3, 4 or 5 R^(h) groups.

In certain embodiments, R^(e) is a C₁₋₆ perhaloalkyl. In certainembodiments, R^(e) is a C₁₋₅ perhaloalkyl. In certain embodiments, R^(e)is a C₁₋₂ perhaloalkyl. In certain embodiments, R^(e) is a C₁₋₃perhaloalkyl. In certain embodiments, R^(e) is a C₁₋₂ perhaloalkyl.Exemplary R^(e) perhaloalkyl groups include, but are not limited to,—CF₃, —CF₂CF₃, —CF₂CF₂CF₃, —CCl₃, —CFCl₂, and —CF₂Cl.

In certain embodiments, R^(e) is C₂₋₁₀ alkenyl. In certain embodiments,R^(e) is C₂₋₆ alkenyl. In certain embodiments, R^(e) is a C₂₋₆ alkenylsubstituted with 0, 1, 2, 3, 4 or 5 R^(h) groups. In certainembodiments, R^(e) is a C₂₋₅ alkenyl substituted with 0, 1, 2, 3, 4 or 5R^(h) groups. In certain embodiments, R^(e) is a C₂₋₃ alkenylsubstituted with 0, 1, 2, or 3 R^(h) groups. Exemplary alkenyl groupsinclude, but are not limited to, ethenyl, 1-propenyl, 2-propenyl,1-butenyl, 2-butenyl, butadienyl, pentenyl, pentadienyl and hexenyl,wherein such groups are substituted with 0, 1, 2, 3, 4 or 5 R^(h)groups.

In certain embodiments, R^(e) is C₂₋₁₀ alkynyl. In certain embodiments,R^(e) is C₂₋₆ alkynyl. In certain embodiments, R^(e) is C₂₋₆ alkynylsubstituted with 0, 1, 2, 3, 4 or 5 R^(h) groups. In certainembodiments, R^(e) is C₂₋₅ alkynyl substituted with 0, 1, 2, 3, 4 or 5R^(h) groups. In certain embodiments, R^(e) is C₂₋₄ alkynyl substitutedwith 0, 1, 2, 3 or 4 R^(h) groups. In certain embodiments, R^(e) is C₂₋₃alkynyl substituted with 0, 1, 2 or 3 R^(h) groups. Exemplary R^(e)alkynyl groups include, but are not limited to, ethynyl, 1-propynyl,2-propynyl, 1-butynyl, 2-butynyl, pentynyl and hexynyl, wherein suchgroups are substituted with 0, 1, 2, 3, 4 or 5 R^(h) groups.

However, in certain embodiments, wherein G is —OR^(e), then R^(e) is notC₁₋₆ alkyl (e.g., methyl, ethyl, propyl, isopropyl, aralkyl). In certainembodiments, wherein G is —OR^(e), then R^(e) is not C₂₋₆ alkenyl (e.g.,allyl).

In certain embodiments, wherein G is —SR^(e), then R^(e) is not thenR^(e) is not C₁₋₆ alkyl (e.g., methyl, ethyl, propyl, isopropyl,aralkyl).

In certain embodiments, wherein G is —NR^(e)R^(f) and R^(f) is —H orC₁₋₃ alkyl (e.g., methyl, ethyl, aralkyl) then R^(e) is not C₁₋₆ alkyl.

In certain embodiments, R^(e) is C₆₋₁₄ aryl. In certain embodiments,R^(e) is C₆₋₁₀ aryl. In certain embodiments, R^(e) is C₆₋₁₀ arylsubstituted with 0, 1, 2, 3, 4 or 5 R^(h) groups. In certainembodiments, R^(e) is C₆ aryl (e.g., phenyl) substituted with 0, 1, 2,3, 4 or 5 R^(h) groups. In certain embodiments, R^(e) is a C₁₀ aryl(e.g., naphthyl) substituted with 0, 1, 2, 3, 4 or 5 R^(h) groups.

In certain embodiments, R^(e) is phenyl. In certain embodiments, R^(e)is phenyl substituted with 0, 1, 2, 3 or 4 R^(h) groups. In certainembodiments, R^(e) is phenyl substituted with 0, 1, 2 or 3 R^(h) groups.In certain embodiments, R^(e) is phenyl substituted with 0, 1 or 2 R^(h)groups. In certain embodiments, R^(e) is phenyl substituted with 0 or 1R^(h) groups. In certain embodiments, R^(e) is a disubstituted phenyl(i.e., substituted with 2 R^(h) groups). In certain embodiments, R^(e)is a monosubstituted phenyl (i.e., substituted with 1 R^(h) group). Incertain embodiments, R^(e) is an unsubstituted phenyl (i.e., substitutedwith 0 R^(h) groups).

In certain embodiments, R^(e) is phenyl substituted with at least oneortho R^(h) group. In certain embodiments, R^(e) is phenyl substitutedwith at least one meta R^(h) group. In certain embodiments, R^(e) isphenyl substituted with at least one para R^(h) group.

In certain embodiments, R^(e) is a phenyl group of the formula:

wherein x is 0, 1, 2, 3, 4 or 5, and R^(h) is as defined below andherein. In certain embodiments, x is 0, 1, 2, 3 or 4. In certainembodiments, x is 0, 1, 2 or 3. In certain embodiments, x is 0, 1 or 2.In certain embodiments, x is 0 or 1. In certain embodiments, x is 3. Incertain embodiments, R^(e) is a disubstituted phenyl group (i.e.,wherein x is 2). In certain embodiments, R^(e) is a monosubstitutedphenyl group (i.e., wherein x is 1). In certain embodiments, R^(e) is anunsubstituted phenyl group (i.e., wherein x is 0).

For example, in certain embodiments, R^(e) is a substituted orunsubstituted phenyl group of any one of the formulae:

wherein R^(h) is as defined below and herein.

In certain embodiments, R^(e) is a naphthyl. In certain embodiments,R^(e) is a naphthyl group of any one of the formulae:

wherein x is 0, 1, 2, 3, 4 or 5, and R^(h) is as defined below andherein. In certain embodiments, x is 0, 1, 2, 3 or 4. In certainembodiments, x is 0, 1, 2 or 3. In certain embodiments, x is 0, 1 or 2.In certain embodiments, x is 0 or 1. In certain embodiments, R^(e) is atrisubstituted naphthyl group (i.e., wherein x is 3). In certainembodiments, R^(e) is a disubstituted naphthyl group (i.e., wherein x is2). In certain embodiments, R^(e) is a monosubstituted naphthyl group(i.e., wherein x is 1). In certain embodiments, R^(e) is anunsubstituted naphthyl group (i.e., wherein x is 0).

For example, in certain embodiments, R^(e) is a substituted orunsubstituted 1-naphthyl group of any one of the formulae:

wherein R^(h) is as defined below and herein.

In certain embodiments, R^(e) is a substituted or unsubstituted2-naphthyl group of any one of the formulae:

wherein R^(h) is as defined below and herein.

However, in certain embodiments, wherein G is —OR^(e), then R^(e) is notC₁₀ aryl (e.g., 1-naphthyl, 2-naphthyl).

In certain embodiments, R^(e) is 5-14 membered heteroaryl. In certainembodiments, R^(e) is a 5-10 membered heteroaryl substituted with 0, 1,2, 3, 4 or 5 R^(h) groups. In certain embodiments, R^(e) is a 5-8membered heteroaryl substituted with 0, 1, 2, 3, 4 or 5 R^(h) groups. Incertain embodiments, R^(e) is a 5-6 membered heteroaryl substituted with0, 1, 2, 3 or 4 R^(h) groups. In certain embodiments, R^(e) is a 9-10membered heteroaryl substituted with 0, 1, 2, 3, 4 or 5 R^(h) groups.

Exemplary R^(e) heteroaryl groups include, but are not limited to,pyrrolyl, furanyl and thiophenyl, imidazolyl, pyrazolyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl,thiadiazolyl, tetrazolyl, pyridinyl (e.g., 2-pyridinyl, 3-pyridinyl,4-pyridinyl), pyridazinyl (e.g., 3-pyridazinyl, 4-pyridazinyl),pyrimidinyl (e.g. 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl),pyrazinyl, triazinyl, tetrazinyl, azepinyl, oxepinyl, thiepinyl,indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl,isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl,benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl,benzisothiazolyl, benzthiadiazolyl, indolizinyl, purinyl,naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl,quinoxalinyl, phthalazinyl, quinazolinyl, phenanthridinyl,dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl andphenazinyl, wherein such groups are substituted with 0, 1, 2, 3, 4 or 5R^(h) groups.

In certain embodiments, R^(e) is a 5-membered heteroaryl. In certainembodiments, R^(e) is a 5-membered heteroaryl substituted with 0, 1, 2or 3 R^(h) groups. In certain embodiments, R^(e) is a 5-memberedheteroaryl selected pyrrolyl, furanyl, thiophenyl, imidazolyl,pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl,oxadiazolyl, thiadiazolyl and tetrazolyl, wherein such groups aresubstituted with 0, 1, 2 or 3 R^(h) groups.

For example, in certain embodiments, R^(e) is a 5-membered heteroaryl ofthe formula:

wherein Y^(a), Y^(b), Y^(c) and Y^(d) are, independently, selected fromCH, CR^(h), O, S, N, or NR^(k), with the proviso that at least one ofY^(a), Y^(b), Y^(c) and Y^(d) is O, S, N or NR^(k), and wherein R^(h)and R^(k) are defined below and herein.

In certain embodiments of the above formula (i-d), Y^(a) is O, S, N, orNR^(k) and Y^(b), Y^(c) and Y^(d) are, independently, selected from CH,CR^(h), NR^(k) or N. In certain embodiments of the above formula (i-d),Y^(a) is O, S, N, or NR^(k) and Y^(b), Y^(c) and Y^(d) are,independently, selected from CH or CR^(h). In certain embodiments of theabove formula (i-d), Y^(a) is O, S, or NR^(k), Y^(c) is N and Y^(b) andY^(d) are, independently, selected from CH or CR^(h).

In certain embodiments of the above formula (i-d), Y^(b) is O, S, orNR^(k) and Y^(a), Y^(c) and Y^(d) are, independently, selected from CH,CR^(h) or N. In certain embodiments of the above formula (i-d), Y^(b) isO, S, or NR^(k) and Y^(a), Y^(c) and Y^(d) are, independently, selectedfrom CH or CR^(h). In certain embodiments of the above formula (i-d),Y^(b) is O, S, or NR^(k), Y^(d) is N and Y^(a) and Y^(c) are,independently, selected from CH or CR^(h).

In certain embodiments, R^(e) is a substituted or unsubstituted5-membered heteroaryl of any one of the formulae:

wherein x is 0, 1 or 2, and R^(h) and R^(k) are as defined below andherein. In certain embodiments, R^(e) is an unsubstituted 5-memberedheteroaryl (i.e., wherein x is 0). In certain embodiments, R^(e) is asubstituted 5-membered heteroaryl (e.g., wherein x is 1 or 2). Incertain embodiments, R^(e) is a monosubstituted 5-membered heteroaryl(i.e., wherein x is 1). In certain embodiments, R^(e) is a disubstituted5-membered heteroaryl (i.e., wherein x is 2). In certain embodiments, xis 0, 1 or 2. In certain embodiments, x is 0 or 1.

However, in certain embodiments, wherein G is —OR^(e), R^(e) is notthiazolyl, e.g., of the formula:

wherein x is 0, 1 or 2, and R^(h) and R^(k) are as defined below andherein.

In certain embodiments, R^(e) is a 6-membered heteroaryl. In certainembodiments, R^(e) is a 6-membered heteroaryl substituted with 0, 1, 2,3 or 4 R^(h) groups. In certain embodiments, R^(e) is a 6-memberedheteroaryl selected from the group consisting of pyridinyl (e.g.,2-pyridinyl, 3-pyridinyl, 4-pyridinyl), pyridazinyl (e.g.,3-pyridazinyl, 4-pyridazinyl), pyrimidinyl (e.g. 2-pyrimidinyl,4-pyrimidinyl, 5-pyrimidinyl), pyrazinyl, triazinyl and tetrazinyl,wherein such groups are substituted with 0, 1, 2, 3 or 4 R^(h) groups.

For example, in certain embodiments, R^(e) is a 6-membered heteroarylgroup of the formula:

wherein W^(a), W^(b), W^(c), W^(d) and W^(e) are, independently,selected from CH, CR^(h) or N, with the proviso that at least one ofW^(a), W^(b), W^(c), W^(d), and W^(e) is N, and wherein R^(h) is asdefined below and herein.

In certain embodiments, R^(e) is a pyrindinyl group. In certainembodiments, R^(e) is a pyrindinyl group substituted with 0, 1, 2, 3 or4 R^(h) groups. For example, in certain embodiments, R^(e) is apyrindinyl group of the formula:

wherein x is 0, 1, 2, 3 or 4, and R^(h) is as defined below and herein.In certain embodiments, R^(e) is an unsubstituted pyrindinyl (i.e.,wherein x is 0). In certain embodiments, R^(e) is a substitutedpyrindinyl (e.g., wherein x is 1, 2, 3 or 4). In certain embodiments,R^(e) is a monosubstituted pyrindinyl (i.e., wherein x is 1). In certainembodiments, R^(e) is a disubstituted pyrindinyl (i.e., wherein x is 2).In certain embodiments, R^(e) is a trisubstituted pyrindinyl (i.e.,wherein x is 3). In certain embodiments, x is 0, 1, 2 or 3. In certainembodiments, x is 0, 1 or 2. In certain embodiments, x is 0 or 1.

In certain embodiments, R^(e) is a 2-pyrindinyl group, e.g., of theformula (i-e) wherein W^(a) is N and W^(b), W^(c), W^(d) and W^(e) are,independently, CH or CR^(h). In certain embodiments R^(e) is a3-pyrindinyl group, e.g., of the formula (i-e) wherein W^(b) is N andW^(a), W^(c), W^(d) and W^(e) are, independently, CH or CR^(h). Incertain embodiments R^(e) is a 4-pyrindinyl group, e.g., of the formula(i-e) wherein W^(c) is N and W^(a), W^(b), W^(d) and W^(e) are,independently, CH or CR^(h).

In certain embodiments, R^(e) is a substituted or unsubstituted2-pyridinyl group of any one of the formulae:

wherein R^(h) is as defined below and herein.

In certain embodiments, R^(e) is a substituted or unsubstituted3-pyridinyl group of any one of the formulae:

wherein R^(h) is as defined below and herein.

In certain embodiments, R^(e) is a substituted or unsubstituted4-pyridinyl group of any one of the formulae:

wherein R^(h) is as defined below and herein.

In certain embodiments, R^(e) is a pyridazinyl group. In certainembodiments, R^(e) is a pyridazinyl group substituted with 0, 1, 2 or 3R^(h) groups. For example, in certain embodiments, R^(e) is apyridazinyl group of the formula:

wherein x is 0, 1, 2 or 3, and R^(h) is as defined below and herein. Incertain embodiments, R^(e) is an unsubstituted pyridazinyl (i.e.,wherein x is 0). In certain embodiments, R^(e) is a substitutedpyridazinyl (e.g., wherein x is 1, 2 or 3). In certain embodiments,R^(e) is a monosubstituted pyridazinyl (i.e., wherein x is 1). Incertain embodiments, R^(e) is a disubstituted pyridazinyl (i.e., whereinx is 2). In certain embodiments, R^(e) is a trisubstituted pyridazinyl(i.e., wherein x is 3). In certain embodiments, x is 0, 1, 2 or 3. Incertain embodiments, x is 0, 1 or 2. In certain embodiments, x is 0 or1.

In certain embodiments, R^(e) is a 3-pyridazinyl group, e.g., of theformula (i-e) wherein W^(a) and W^(b) are N and W^(c), W^(d) and W^(e)are, independently, CH or CR^(h). In certain embodiments R^(e) is a4-pyridazinyl group, e.g., of the formula (i-e) wherein W^(b) and W^(c)are N and W^(a), W^(d) and W^(e) are, independently, CH or CR^(h).

In certain embodiments, R^(e) is a substituted or unsubstituted3-pyridazinyl group of any one of the formulae:

wherein R^(h) is as defined below and herein.

In certain embodiments, R^(e) is a substituted or unsubstituted4-pyridazinyl group of any one of the formulae:

wherein R^(h) is as defined below and herein.

In certain embodiments, R^(e) is a pyrimidinyl group. In certainembodiments, R^(e) is a pyrimidinyl group substituted with 0, 1, 2 or 3R^(h) groups. For example, in certain embodiments, R^(e) is apyrimidinyl group of the formula:

wherein x is 0, 1, 2 or 3, and R^(h) is as defined below and herein. Incertain embodiments, R^(e) is an unsubstituted pyrimidinyl (i.e.,wherein x is 0). In certain embodiments, R^(e) is a substitutedpyrimidinyl (e.g., wherein x is 1, 2 or 3). In certain embodiments,R^(e) is a monosubstituted pyrimidinyl (i.e., wherein x is 1). Incertain embodiments, R^(e) is a disubstituted pyridazinyl (i.e., whereinx is 2). In certain embodiments, R^(e) is a trisubstituted pyrimidinyl(i.e., wherein x is 3). In certain embodiments, x is 0, 1, 2 or 3. Incertain embodiments, x is 0, 1 or 2. In certain embodiments, x is 0 or1.

In certain embodiments, R^(e) is a 2-pyrimidinyl group, e.g., of theformula (i-e) wherein W^(a) and W^(e) are N and W^(b), W^(c) and W^(d)are, independently, CH or CR^(h). In certain embodiments R^(e) is a4-pyrimidinyl group, e.g., of the formula (i-e) wherein W^(a) and W^(c)are N and W^(b), W^(d) and W^(e) are, independently, CH or CR^(h). Incertain embodiments R^(e) is a 5-pyrimidinyl group, e.g., of the formula(i-e) wherein W^(b) and W^(d) are N and W^(a), W^(c) and W^(e) are,independently, CH or CR^(h).

In certain embodiments, R^(e) is a substituted or unsubstituted2-pyrimidinyl group of any one of the formulae:

wherein R^(h) is as defined below and herein.

In certain embodiments, R^(e) is a substituted or unsubstituted4-pyrimidinyl group of any one of the formulae:

wherein is as defined below and herein.

In certain embodiments, R^(e) is a substituted or unsubstituted5-pyrimidinyl group of any one of the formulae:

wherein R^(h) is as defined below and herein.

In certain embodiments, R^(e) is a pyrazinyl group. In certainembodiments, R^(e) is a pyrazinyl group substituted with 0, 1, 2 or 3R^(h) groups. For example, in certain embodiments, R^(e) is a pyrazinylgroup of the formula:

wherein x is 0, 1, 2 or 3, and R^(h) is as defined below and herein. Incertain embodiments, R^(e) is an unsubstituted pyrazinyl (i.e., whereinx is 0). In certain embodiments, R^(e) is a substituted pyrazinyl (e.g.,wherein x is 1, 2 or 3). In certain embodiments, R^(e) is amonosubstituted pyrazinyl (i.e., wherein x is 1). In certainembodiments, R^(e) is a disubstituted pyrazinyl (i.e., wherein x is 2).In certain embodiments, R^(e) is a trisubstituted pyrazinyl (i.e.,wherein x is 3). In certain embodiments, x is 0, 1, 2 or 3. In certainembodiments, x is 0, 1 or 2. In certain embodiments, x is 0 or 1.

In certain embodiments, R^(e) is a substituted or unsubstitutedpyrazinyl group of any one of the formulae:

wherein R^(h) is as defined below and herein.

In certain embodiments R^(e) is a triazinyl group. In certainembodiments R^(e) is a triazinyl group substituted with 0, 1 or 2 R^(h)groups. For example, in certain embodiments, R^(e) is a triazinyl groupof the formula:

wherein x is 0, 1 or 2, and R^(h) is as defined below and herein. Incertain embodiments, R^(e) is an unsubstituted pyrazinyl (i.e., whereinx is 0). In certain embodiments, R^(e) is a substituted pyrazinyl (e.g.,wherein x is 1 or 2). In certain embodiments, R^(e) is a monosubstitutedpyrazinyl (i.e., wherein x is 1). In certain embodiments, R^(e) is adisubstituted pyrazinyl (i.e., wherein x is 2). In certain embodiments,x is 0, 1 or 2. In certain embodiments, x is 0 or 1.

In certain embodiments, R^(e) is a substituted or unsubstitutedtriazinyl group of any one of the formulae:

wherein R^(h) is as defined below and herein.

In certain embodiments R^(e) is a tetrazinyl group. In certainembodiments R^(e) is a tetrazinyl group substituted with 0 or 1 R^(h)groups. For example, in certain embodiments, R^(e) is a tetrazinyl groupof the formula:

wherein x is 0 or 1, and R^(h) is as defined below and herein. Incertain embodiments, R^(e) is an unsubstituted pyrazinyl (i.e., whereinx is 0). In certain embodiments, R^(e) is a substituted pyrazinyl (e.g.,wherein x is 1). In certain embodiments, x is 0 or 1.

In certain embodiments, R^(e) is a substituted or unsubstitutedtetrazinyl group of any one of the formulae:

wherein R^(h) is as defined below and herein.

In certain embodiments, R^(e) is a 9-membered heteroaryl (e.g., a5,6-bicyclic heteroaryl). In certain embodiments, R^(e) is a5,6-bicyclic heteroaryl substituted with 0, 1, 2, 3, 4 or 5 R^(h)groups. In certain embodiments, R^(e) is a 5,6-bicyclic heteroarylselected from indolyl, isoindolyl, indazolyl, benzotriazolyl,benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl,benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl,benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, andpurinyl, wherein such groups are substituted with 0, 1, 2, 3, 4 or 5R^(h) groups.

For example, in certain embodiments, R^(e) is a 5,6-bicyclic heteroarylof the formula:

wherein Y^(e), Y^(f), Y^(g), Y^(i), Y^(k) and Y^(m) are, independently,C, CH, CR^(h), O, S, N, or NR^(k) and V is C or N, with the proviso thatat least one of Y^(e), Y^(f), Y^(g) is selected from O, S, N or NR^(k)wherein R^(h) and R^(k) are as defined below and herein.

In certain embodiments, R^(e) is a 5,6-bicyclic heteroaryl group of theformula (i-f), wherein Y^(e) is selected from O, S, or NR^(k), V is C,and Y^(f), Y^(g), Y^(i), Y^(j), Y^(k) and Y^(m) are, independently, C,CH, or CR^(h). For example, in certain embodiments, R^(e) is a5,6-bicyclic heteroaryl group of the formulae:

wherein x is 0, 1, 2, 3, 4 or 5 and R^(h) and R^(k) are defined belowand herein. In certain embodiments, R^(e) is an unsubstituted5,6-bicyclic heteroaryl (i.e., wherein x is 0). In certain embodiments,R^(e) is a substituted 5,6-bicyclic heteroaryl (e.g., wherein x is 1, 2,3, 4 or 5). In certain embodiments, R^(e) is a monosubstituted5,6-bicyclic heteroaryl (i.e., wherein x is 1). In certain embodiments,R^(e) is a disubstituted 5,6-bicyclic heteroaryl (i.e., wherein x is 2).In certain embodiments, R^(e) is a trisubstituted 5,6-bicyclicheteroaryl (i.e., wherein x is 3). In certain embodiments, x is 0, 1, 2or 3. In certain embodiments, x is 0, 1 or 2. In certain embodiments, xis 0 or 1.

In certain embodiments, R^(e) is a 5,6-bicyclic heteroaryl wherein Y^(e)is selected from O, S, or NR^(k); Y^(g) is N; V is C; Y^(f) is C, CH, orCR^(h) or N, and Y^(i), Y^(j), Y^(k) and Y^(m) are, independently, C,CH, or CR^(h). For example, in certain embodiments, R^(e) is a5,6-bicyclic heteroaryl group of the formulae:

wherein x is 0, 1, 2, 3, 4 or 5 and R^(h) and R^(k) are defined belowand herein. In certain embodiments, R^(e) is an unsubstituted5,6-bicyclic heteroaryl (i.e., wherein x is 0). In certain embodiments,R^(e) is a substituted 5,6-bicyclic heteroaryl (e.g., wherein x is 1, 2,3, 4 or 5). In certain embodiments, R^(e) is a monosubstituted5,6-bicyclic heteroaryl (i.e., wherein x is 1). In certain embodiments,R^(e) is a disubstituted 5,6-bicyclic heteroaryl (i.e., wherein x is 2).In certain embodiments, R^(e) is a trisubstituted 5,6-bicyclicheteroaryl (i.e., wherein x is 3). In certain embodiments, x is 0, 1, 2or 3. In certain embodiments, x is 0, 1 or 2. In certain embodiments, xis 0 or 1.

In certain embodiments, R^(e) is a 5,6-bicyclic heteroaryl wherein Y^(e)is NR^(k), S or O; Y^(m) is N; Y^(n) is C; and Y^(f), Y^(g), Y^(i),Y^(j), and Y^(k) are, independently, C, CH, or CR^(h). For example, incertain embodiments, R^(e) is a 5,6-bicyclic heteroaryl group of theformulae:

wherein x is 0, 1, 2, 3, 4 or 5 and R^(h) and R^(k) are defined belowand herein. In certain embodiments, R^(e) is an unsubstituted5,6-bicyclic heteroaryl (i.e., wherein x is 0). In certain embodiments,R^(e) is a substituted 5,6-bicyclic heteroaryl (e.g., wherein x is 1, 2,3, 4 or 5). In certain embodiments, R^(e) is a monosubstituted5,6-bicyclic heteroaryl (i.e., wherein x is 1). In certain embodiments,R^(e) is a disubstituted 5,6-bicyclic heteroaryl (i.e., wherein x is 2).In certain embodiments, R^(e) is a trisubstituted 5,6-bicyclicheteroaryl (i.e., wherein x is 3). In certain embodiments, x is 0, 1, 2or 3. In certain embodiments, x is 0, 1 or 2. In certain embodiments, xis 0 or 1.

In certain embodiments, R^(e) is a 5,6-bicyclic heteroaryl wherein Y^(g)is O, S, or NR^(k); Y^(m) is N; V is C; and Y^(e), Y^(f), Y^(i), Y^(j)and Y^(k) are, independently, C, CH, or CR^(h). For example, in certainembodiments, R^(e) is a 5,6-bicyclic heteroaryl group of the formulae:

wherein x is 0, 1, 2, 3, 4 or 5 and R^(h) and R^(k) are defined belowand herein. In certain embodiments, R^(e) is an unsubstituted5,6-bicyclic heteroaryl (i.e., wherein x is 0). In certain embodiments,R^(e) is a substituted 5,6-bicyclic heteroaryl (e.g., wherein x is 1, 2,3, 4 or 5). In certain embodiments, R^(e) is a monosubstituted5,6-bicyclic heteroaryl (i.e., wherein x is 1). In certain embodiments,R^(e) is a disubstituted 5,6-bicyclic heteroaryl (i.e., wherein x is 2).In certain embodiments, R^(e) is a trisubstituted 5,6-bicyclicheteroaryl (i.e., wherein x is 3). In certain embodiments, x is 0, 1, 2or 3. In certain embodiments, x is 0, 1 or 2. In certain embodiments, xis 0 or 1.

In certain embodiments, R^(e) is a 5,6-bicyclic heteroaryl wherein Y^(e)is selected from N; Y^(n) is N; and Y^(f), Y^(i), Y^(j), Y^(k) and Y^(m)are, independently, C, CH, or CR^(h). For example, in certainembodiments, R^(e) is a 5,6-bicyclic heteroaryl group of the formula:

wherein x is 0, 1, 2, 3, 4 or 5 and R^(h) and R^(k) are defined belowand herein. In certain embodiments, R^(e) is an unsubstituted5,6-bicyclic heteroaryl (i.e., wherein x is 0). In certain embodiments,R^(e) is a substituted 5,6-bicyclic heteroaryl (e.g., wherein x is 1, 2,3, 4 or 5). In certain embodiments, R^(e) is a monosubstituted5,6-bicyclic heteroaryl (i.e., wherein x is 1). In certain embodiments,R^(e) is a disubstituted 5,6-bicyclic heteroaryl (i.e., wherein x is 2).In certain embodiments, R^(e) is a trisubstituted 5,6-bicyclicheteroaryl (i.e., wherein x is 3). In certain embodiments, x is 0, 1, 2or 3. In certain embodiments, x is 0, 1 or 2. In certain embodiments, xis 0 or 1.

In certain embodiments, R^(e) is a 10-membered heteroaryl (e.g., a6,6-bicyclic heteroaryl). In certain embodiments, R^(e) is a6,6-bicyclic heteroaryl substituted with 0, 1, 2, 3, 4 or 5 R^(h)groups. In certain embodiments, R^(e) is a 6,6-bicyclic heteroarylselected from naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl,cinnolinyl, quinoxalinyl, phthalazinyl and quinazolinyl, wherein suchgroups are substituted with 0, 1, 2, 3, 4 or 5 R^(h) groups.

For example, in certain embodiments, R^(e) is a 6,6-bicyclic heteroarylof the formula:

wherein W^(f), W^(g), W^(h), W^(i), W^(j), W^(k), W^(m) and are,independently, selected from C, CH, CR^(h) or N, with the proviso thatat least one of W^(f), W^(g), W^(h), W^(i), W^(j), W^(k), W^(m) andW^(n) is N, and wherein R^(h) is as defined below and herein.

In certain embodiments, R^(e) is a quinolinyl group; e.g., of theformula (i-g) wherein W^(i) is N and W^(g), W^(h), W^(f), W^(j), W^(k),W^(m) and W^(n) are, independently, C, CH, or CR^(h). For example, incertain embodiments, R^(e) is a quinolinyl group of the formulae:

wherein x is 0, 1, 2, 3, 4 or 5, and R^(h) is as defined below andherein. In certain embodiments, R^(e) is an unsubstituted quinolinyl(i.e., wherein x is 0). In certain embodiments, R^(e) is a substitutedquinolinyl (e.g., wherein x is 1, 2, 3, 4 or 5). In certain embodiments,R^(e) is a monosubstituted quinolinyl (i.e., wherein x is 1). In certainembodiments, R^(e) is a disubstituted quinolinyl (i.e., wherein x is 2).In certain embodiments, R^(e) is a trisubstituted quinolinyl (i.e.,wherein x is 3). In certain embodiments, x is 0, 1, 2 or 3. In certainembodiments, x is 0, 1 or 2. In certain embodiments, x is 0 or 1.

In certain embodiments, R^(e) is an isoquinolinyl group; e.g., of theformula (i-g) wherein W^(h) is N and W^(f), W^(g), W^(i), W^(j), W^(k),W^(m) and are, independently, C, CH, or CR^(h). For example, in certainembodiments, R^(e) is an isoquinolinyl group of the formulae:

wherein x is 0, 1, 2, 3, 4 or 5, and R^(h) is as defined below andherein. In certain embodiments, R^(e) is an unsubstituted isoquinolinyl(i.e., wherein x is 0). In certain embodiments, R^(e) is a substitutedisoquinolinyl (e.g., wherein x is 1, 2, 3, 4 or 5). In certainembodiments, R^(e) is a monosubstituted isoquinolinyl (i.e., wherein xis 1). In certain embodiments, R^(e) is a disubstituted isoquinolinyl(i.e., wherein x is 2). In certain embodiments, R^(e) is atrisubstituted isoquinolinyl (i.e., wherein x is 3). In certainembodiments, x is 0, 1, 2 or 3. In certain embodiments, x is 0, 1 or 2.In certain embodiments, x is 0 or 1.

In certain embodiments, R^(e) is a quinoxalinyl group; e.g., of theformula (i-g) wherein W^(f) and W^(i) are N and W^(g), W^(h), W^(j),W^(k), W^(m) and are, independently, C, CH, or CR^(h). For example, incertain embodiments, R^(e) is a quinoxalinyl group of the formulae:

wherein x is 0, 1, 2, 3, 4 or 5, and R^(h) is as defined below andherein. In certain embodiments, R^(e) is an unsubstituted quinoxalinyl(i.e., wherein x is 0). In certain embodiments, R^(e) is a substitutedquinoxalinyl (e.g., wherein x is 1, 2, 3, 4 or 5). In certainembodiments, R^(e) is a monosubstituted quinoxalinyl (i.e., wherein x is1). In certain embodiments, R^(e) is a disubstituted quinoxalinyl (i.e.,wherein x is 2). In certain embodiments, R^(e) is a trisubstitutedquinoxalinyl (i.e., wherein x is 3). In certain embodiments, x is 0, 1,2 or 3. In certain embodiments, x is 0, 1 or 2. In certain embodiments,x is 0 or 1.

In certain embodiments, R^(e) is a 3-14 membered heterocyclyl. Incertain embodiments, R^(e) is a 3-14 membered heterocyclyl substitutedwith 0, 1, 2, 3, 4 or 5 R^(h) groups. In certain embodiments, R^(e) is a5-10 membered heterocyclyl substituted with 0, 1, 2, 3, 4 or 5 R^(h)groups. In certain embodiments, R^(e) is a 5-8 membered heterocyclylsubstituted with 0, 1, 2, 3, 4 or 5 R^(h) groups. In certainembodiments, R^(e) is a 5-6 membered heterocyclyl substituted with 0, 1,2, 3, 4 or 5 R^(h) groups. In certain embodiments, R^(e) is a 9-10membered heterocyclyl substituted with 0, 1, 2, 3, 4 or 5 R^(h) groups.

Exemplary heterocyclyl R^(e) groups include, but are not limited to,azirdinyl, oxiranyl, thiorenyl, azetidinyl, oxetanyl, thietanyl,tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl,dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, pyrrolyl-2,5-dione,dioxolanyl, oxathiolanyl, dithiolanyl, triazolinyl, oxadiazolinyl,thiadiazolinyl, piperidinyl, tetrahydropyranyl, dihydropyridinyl,thianyl, piperazinyl, morpholinyl, dithianyl, dioxanyl, triazinanyl,azepanyl, oxepanyl, thiepanyl, azocanyl, oxecanyl, thiocanyl, indolinyl,isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl,tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl,tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl,decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl,decahydronaphthyridinyl, decahydro-1,8-naphthyridinyl,octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl,chromanyl, chromenyl, 1H-benzo[e][1,4]diazepinyl,1,4,5,7-tetrahydro-pyrano[3,4-b]pyrrolyl,5,6-dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl,5,7-dihydro-4H-thieno[2,3-c]pyranyl,2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3-b]pyridinyl,4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridinyl,4,5,6,7-tetra-hydrofuro[3,2-c]pyridinyl, and4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl,1,2,3,4-tetrahydro-1,6-naphthyridinyl, wherein such groups aresubstituted with 0, 1, 2, 3, 4 or 5 R^(h) groups.

In certain embodiments, R^(e) is a 6-membered heterocyclyl substitutedwith 0, 1, 2, 3, 4 or 5 R^(h) groups. In certain embodiments, R^(e) is a6-membered heterocyclyl selected from piperidinyl, tetrahydropyranyl,dihydropyridinyl, thianyl, piperazinyl, morpholinyl, dithianyl,dioxanyl, and triazinanyl, wherein such groups are substituted with 0,1, 2, 3, 4 or 5 R^(h) groups.

For example, in certain embodiments, R^(e) is a 6-membered heterocyclylof the formula:

wherein W^(o), W^(p), W^(q), W^(r), and W^(s) are, independently,selected from CH₂, CHR^(h), C(R^(h))₂, NR^(k), O or S, and W^(t) is N,CH, CR^(h), with the proviso that at least one of W^(o), W^(p), W^(q),W^(r) and W^(s) is selected from N, NR^(k), O or S, and wherein R^(h)and R^(k) are defined below and herein.

In certain embodiments, R^(e) is a piperidinyl group. In certainembodiments, R^(e) is a piperidinyl group substituted with 0, 1, 2, 3, 4or 5 R^(h) groups, e.g., of the formulae:

wherein x is 0, 1, 2, 3, 4 or 5, and R^(h) and R^(k) are as definedbelow and herein. In certain embodiments, R^(e) is an unsubstitutedpiperidinyl (i.e., wherein x is 0). In certain embodiments, R^(e) is asubstituted piperidinyl (e.g., wherein x is 1, 2, 3, 4 or 5). In certainembodiments, R^(e) is a monosubstituted piperidinyl (i.e., wherein x is1). In certain embodiments, R^(e) is a disubstituted piperidinyl (i.e.,wherein x is 2). In certain embodiments, R^(e) is a trisubstitutedpiperidinyl (i.e., wherein x is 3). In certain embodiments, x is 0, 1, 2or 3. In certain embodiments, x is 0, 1 or 2. In certain embodiments, xis 0 or 1.

In certain embodiments, R^(e) is a 1-piperidinyl group, e.g., of theformula (i-h) wherein W^(t) is N and W^(o), W^(p), W^(q), W^(r), andW^(s) are, independently, selected from CH₂, CHR^(h), C(R^(h))₂. Incertain embodiments, R^(e) is a 2-piperidinyl group, e.g., of theformula (i-h) wherein W^(o) is NR^(k); W^(p), W^(q), W^(r), and W^(s)are, independently, CHR^(h), C(R^(h))₂, or CH₂; and W^(t) is CH orCR^(h). In certain embodiments, R^(e) is a 3-piperidinyl group, e.g., ofthe formula (i-h) wherein W^(p) is NR^(k); W^(o), W^(q), Q^(f), andW^(s) are, independently, CHR^(h), C(R^(h))₂, or CH₂; and W^(t) is CH orCR^(h). In certain embodiments, R^(e) is a 4-piperidinyl group, e.g., ofthe formula (i-h) wherein W^(q) is NR^(k); W^(o), W^(p), W^(r), andW^(s) are, independently, CHR^(h), C(R^(h))₂, or CH₂; and W^(t) is CH orCR^(h).

In certain embodiments, R^(e) is a piperazinyl group. In certainembodiments, R^(e) is a piperazinyl group substituted with 0, 1, 2, 3 or4 R^(h) groups, e.g., of the formulae:

wherein x is 0, 1, 2, 3, 4 or 5, and R^(h) and R^(k) are as definedbelow and herein. In certain embodiments, R^(e) is an unsubstitutedpiperazinyl (i.e., wherein x is 0). In certain embodiments, R^(e) is asubstituted piperazinyl (e.g., wherein x is 1, 2, 3, 4 or 5). In certainembodiments, R^(e) is a monosubstituted piperazinyl (i.e., wherein x is1). In certain embodiments, R^(e) is a disubstituted piperazinyl (i.e.,wherein x is 2). In certain embodiments, R^(e) is a trisubstitutedpiperazinyl (i.e., wherein x is 3). In certain embodiments, x is 0, 1, 2or 3. In certain embodiments, x is 0, 1 or 2. In certain embodiments, xis 0 or 1.

In certain embodiments, R^(e) is a 1-piperazinyl group, e.g., of theformula (i-h) wherein W^(t) is N, W^(q) is NR^(k) and W^(o), W^(p),W^(r), and W^(s) are, independently, selected from CH₂, CHR^(h),C(R^(h))₂. In certain embodiments, R^(e) is a 2-piperazinyl group, e.g.,of the formula (i-h) wherein W^(o) and W^(r) are independently NR^(k)and W^(p), W^(q), W^(r), and W^(s) are, independently, CHR^(h),C(R^(h))₂, or CH₂; and W^(t) is CH or CR^(h).

In certain embodiments, R^(e) is a morpholinyl group. In certainembodiments, R^(e) is a morpholinyl group substituted with 0, 1, 2, 3 or4 R^(h) groups, e.g., of the formulae:

wherein x is 0, 1, 2, 3, 4 or 5, and R^(h) and R^(k) are as definedbelow and herein. In certain embodiments, R^(e) is an unsubstitutedmorpholinyl (i.e., wherein x is 0). In certain embodiments, R^(e) is asubstituted morpholinyl (e.g., wherein x is 1, 2, 3, 4 or 5). In certainembodiments, R^(e) is a monosubstituted morpholinyl (i.e., wherein x is1). In certain embodiments, R^(e) is a disubstituted morpholinyl (i.e.,wherein x is 2). In certain embodiments, R^(e) is a trisubstitutedmorpholinyl (i.e., wherein x is 3). In certain embodiments, x is 0, 1, 2or 3. In certain embodiments, x is 0, 1 or 2. In certain embodiments, xis 0 or 1.

In certain embodiments, R^(e) is a morpholinyl group of the formula(i-h) wherein W^(t) is N, W^(q) is O and W^(o), W^(p), W^(r), and W^(s)are, independently, selected from CH₂, CHR^(h), C(R^(h))₂.

In certain embodiments, R^(e) is a dioxanyl group. In certainembodiments, R^(e) is a dioxanyl group substituted with 0, 1, 2, 3 or 4R^(h) groups, e.g., of the formulae:

wherein x is 0, 1, 2, 3, 4 or 5, and R^(h) and R^(k) are as definedbelow and herein. In certain embodiments, R^(e) is an unsubstituteddioxanyl (i.e., wherein x is 0). In certain embodiments, R^(e) is asubstituted dioxanyl (e.g., wherein x is 1, 2, 3, 4 or 5). In certainembodiments, R^(e) is a monosubstituted dioxanyl (i.e., wherein x is 1).In certain embodiments, R^(e) is a disubstituted dioxanyl (i.e., whereinx is 2). In certain embodiments, R^(e) is a trisubstituted dioxanyl(i.e., wherein x is 3). In certain embodiments, x is 0, 1, 2 or 3. Incertain embodiments, x is 0, 1 or 2. In certain embodiments, x is 0 or1.

In certain embodiments, R^(e) is a dioxanyl group, e.g., of the formula(i-h) wherein W^(o) and W^(r) are O and W^(p), W^(q), W^(r), and W^(s)are, independently, CHR^(h), C(R^(h))₂, or CH₂; and W^(t) is CH orCR^(h).

Other 6-membered heterocycyl R^(e) groups encompassed by formula (i-h)include monosaccharide sugars, e.g., for example, pyranosides selectedfrom ribose, arabinose, xylose, lyxose, allose, altrose, glucose,mannose, gulose, iodose, galactose and talose.

In certain embodiments, R^(e) is a C₃₋₁₀ carbocycyl. In certainembodiments, R^(e) is a C3-10 carbocycyl substituted with 0, 1, 2, 3, 4,or 5 R^(h) groups. In certain embodiments, R^(e) is a C5-8 carbocycylsubstituted with 0, 1, 2, 3, 4, or 5 R^(h) groups. In certainembodiments, R^(e) is a C5-6 carbocycyl substituted with 0, 1, 2, 3 or 4R^(h) groups. In certain embodiments, R^(e) is a C9-10 carbocycylsubstituted with 0, 1, 2, 3, 4, or 5 R^(h) groups.

Exemplary R^(e)C₃₋₁₀ carbocycyl groups include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl,cyclohexenyl, cyclohexadienyl, cycloheptyl, and cycloheptadienyl,wherein such groups are substituted with 0, 1, 2, 3, 4, or 5 R^(h)groups.

R^(f) of Group G

As defined generally above, in certain embodiments, wherein G isselected from —SO₂NR^(f)R^(e), —PO₂NR^(f)R^(e), —(C═O)NR^(f)R^(e),—ONR^(f)R^(e), —ONR^(f)(C═O)R^(e), —ONR^(f)SO₂R^(e), —ONR^(f)PO₂R^(e),—ONR^(f)PO₂OR^(e), —NR^(f)SO₂R^(e), —NR^(f)PO₂R^(e), —NR^(f)PO₂OR^(e),—OPO₂NR^(f)R^(e), —NR^(f)R^(e), —NR^(f)(C═O)R^(e), —NR^(f)(C═O)OR^(e),—O(C═O)NR^(f)R^(e), —NR^(f)(C═NR^(f))NR^(f)R^(e),—O(C═NR^(f))NR^(f)R^(e), —NR^(f)(C═NR^(f))OR^(e), and—[N(R^(f))₂R^(e)]⁺X⁻ wherein X⁻ is a counterion, each R^(f) attached toa nitrogen atom is, independently, selected from —H or C₁₋₁₀ alkyl, oran amino protecting group, or R^(e) and R^(f) are joined to form an 3-14membered heterocyclyl ring or an 5-14 membered heteroaryl ring.

In certain embodiments, R^(f) is H or a C₁₋₁₀ alkyl group.

In certain embodiments, R^(f) is H.

In certain embodiments, R^(f) is a C₁₋₁₀ alkyl group. In certainembodiments, R^(f) is C₁₋₁₀ alkyl substituted with 0, 1, 2, 3, 4, or 5R^(h) groups. Exemplary R^(f) alkyl groups include, but are not limitedto, methyl, ethyl, propyl, allyl, and benzyl. In certain embodiments,R^(f) an unsubstituted methyl, i.e., —CH₃. In certain embodiments, R^(f)an unsubstituted ethyl, i.e., —CH₂CH₃.

In certain embodiments, R^(f) is an amino protecting group. For example,in certain embodiments, R^(f) is selected from —OH, —OR^(i), —N(R^(k))₂,—C(═O)R^(i), —C(═O)N(R^(k))₂, —CO₂R^(i), —SO₂R^(i), —C(═NR^(k))R^(i),—C(═NR^(k))OR^(j), —C(═NR^(k))N(R^(k))₂, —SO₂N(R^(k))₂, —SO₂R^(i),—SO₂OR^(i), —SOR^(i), —C(═S)N(R^(k))₂, —C(═O)SR^(i), —C(═S)SR^(i), C₁₋₁₀alkyl (e.g., aralkyl), C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocyclyl,3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroarylgroups, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl,aralkyl, aryl, and heteroaryl is independently substituted with 0, 1, 2,3, 4, or 5 R^(m) groups, wherein R^(k), R^(m) are as defined below andherein.

However, in certain embodiments, G is —NR^(e)R^(f) and R^(f) is —H orC₁₋₃ alkyl, then R^(e) is not C₁₋₆ alkyl or thiazolyl.

Moreover, in certain embodiments, wherein G is —OC(═O)NR^(f)R^(e), thenR^(e) and R^(f) are not both —CH₃.

Alternatively, in certain embodiments, R^(e) and R^(f) are joined toform an 3-14 membered heterocyclyl ring or an 5-14 membered heteroarylring; e.g., for example, when G is —SO₂NR^(f)R^(e), —PO₂NR^(f)R^(e),—(C═O)NR^(f)R^(e), —ONR^(f)R^(e), —OPO₂NR^(f)R^(e), —NR^(f)R^(e),—O(C═O)NR^(f)R^(e), —NR^(f)(C═NR^(f))NR^(f)R^(e), —O(C═NR)NR^(f)R^(e),and —[N(R^(f))₂R^(e)]⁺X⁻ wherein X⁻ is a counterion. In certainembodiments, wherein R^(e) and R^(f) are joined to form an 3-14 memberedheterocyclyl ring or an 5-14 membered heteroaryl ring, the heterocyclylring or heteroaryl ring are substituted with 0, 1, 2, 3, 4 or 5 R^(h)groups, as defined below and herein.

In certain embodiments, R^(e) and R^(f) are joined to form an 3-14membered heterocyclyl ring. In certain embodiments, R^(e) and R^(f) arejoined to form a 3-14 membered heterocyclyl ring substituted with 0, 1,2, 3, 4 or 5 R^(h) groups. In certain embodiments, and R^(f) are joinedto form a 5-10 membered heterocyclyl ring substituted with 0, 1, 2, 3,4, or 5 R^(h) groups. In certain embodiments, R^(e) and R^(f) are joinedto form a 5-8 membered heterocyclyl ring substituted with 0, 1, 2, 3, 4,or 5 R^(h) groups. In certain embodiments, R^(e) and R^(f) are joined toform a 5-6 membered heterocyclyl ring substituted with 0, 1, 2 or 3R^(h) groups. In certain embodiments, R^(e) and R^(f) are joined to forma 9-10 membered heterocyclyl ring substituted with 0, 1, 2, 3, 4, or 5R^(h) groups.

In certain embodiments, R^(e) and R^(f) are joined to form aheterocyclyl group selected from azirdinyl, azetidinyl, pyrrolidinyl,dihydropyrrolyl, pyrrolyl-2,5-dione, triazolinyl, oxadiazolinyl,thiadiazolinyl, piperidinyl, dihydropyridinyl, thianyl, piperazinyl,morpholinyl, triazinanyl, azepanyl, oxepanyl, thiepanyl, azocanyl,indolinyl, isoindolinyl, tetrahydrobenzo-thienyl, tetrahydroindolyl,tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl,decahydroisoquinolinyl, indolinyl, and phthalimidyl, wherein such groupsare substituted with 0, 1, 2, 3, 4 or 5 R^(h) groups.

For example, in certain embodiments, R^(e) and R^(f) are joined to forma 5-membered heterocyclyl ring selected from the group:

wherein x is 0, 1, 2 or 3, wherein R^(h) and R^(k) are as defined belowand herein.

In certain embodiments, R^(e) and R^(f) are joined to form a 6-memberedheterocyclyl ring selected from the group:

wherein x is 0, 1, 2 or 3, wherein R^(h) and R^(k) are as defined belowand herein.

However, in certain embodiments, wherein G is —NR^(e)R^(f), then R^(e)and R^(f) are not joined to form a pyrrolidinyl, piperidinyl or azepanylring.

In certain embodiments, R^(e) and R^(f) are joined to form a 5-14membered heteroaryl ring. In certain embodiments, R^(e) and R^(f) arejoined to form a 5-14 membered heteroaryl ring substituted with 0, 1, 2,3, 4, or 5 R^(h) groups. In certain embodiments, R^(e) and R^(f) arejoined to form a 5-10 membered heteroaryl ring substituted with 0, 1, 2,3, 4, or 5 R^(h) groups. In certain embodiments, R^(e) and R^(f) arejoined to form a 5-8 membered heteroaryl ring substituted with 0, 1, 2,3 or 4 R^(h) groups. In certain embodiments, R^(e) and R^(f) are joinedto form a 5-6 membered heteroaryl ring substituted with 0, 1, 2, 3 or 4R^(h) groups. In certain embodiments, R^(e) and R^(f) are joined to forma 9-10 membered heteroaryl ring substituted with 0, 1, 2, 3, 4, or 5R^(h) groups.

In certain embodiments, R^(e) and R^(f) are joined to form a 5-memberedheteroaryl ring selected from:

wherein x is 0, 1 or 2, and R^(h) and R^(k) are as defined below andherein.

However, in certain embodiments, wherein G is —NR^(f)R^(e), R^(e) andR^(f) are not joined to form a 1,2,4-triazolyl ring, e.g. of theformula:

wherein x is 0 or 1, and R^(h) is as defined below and herein.

In certain embodiments, R^(e) and R^(f) are joined to form a 9-memberedheteroaryl (“5,6-bicyclic heteroaryl”) ring selected from:

wherein x is 0, 1, 2 or 3 and R^(h) and R^(k) are as defined below andherein.

Group G Substituents Embodiments of R^(h)

As used above and herein each instance of R^(h) is, independently,selected from halogen (fluoro (—F), bromo (—Br), chloro (—Cl), and iodo(—I)), —CN, —NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR^(i), —ON(R^(k))₂,—N(R^(k))₂, —N(R^(k))₃—N(OR^(j))R^(k), —SH, —SSR^(j), —C(═O)R^(i),—CO₂H, —CHO, —CO₂R^(i), —OC(═O)R^(i), —OCO₂R^(i), —C(═O)N(R^(k))₂,—OC(═O)N(R^(i))₂, —NR^(k)C(═O)R^(i), —NR^(k)CO₂R^(i),—NR^(k)C(═O)N(R^(k))₂, —C(═NR^(k))R^(i), —C(═NR^(k))OR^(i),—OC(═NR^(k))R^(i), —OC(═NR^(k))OR^(i), —C(═NR^(k))N(R^(k))₂,—OC(═NR^(k))N(R^(k))₂, —NR^(k)C(═NR^(k))N(R^(k))₂, —C(═O)NR^(k)SO₂R^(i),—NR^(i)SO₂Ri, —SO₂N(R^(k))₂, —SO₂R^(i), —SO₂OR^(i), —OSO₂R^(i),—S(═O)R^(i), —OS(═O)R^(i), —Si(R^(i))₃, —OS^(i)(Ri)₃ —C(═S)N(R^(k))₂,—C(═O)SR^(i), —C(═S)SR^(i), —SC(S)SR^(i), —P(═O)₂R^(i), —OP(═O)₂R^(i),—P(═O)(R^(i))₂, —OP(═O)(R^(i))₂, —OP(═O)(OR^(j))₂, —P(═O)₂N(R^(k))₂,—OP(═O)₂N(R^(k))₂, —P(═O)(NR^(k))₂, —OP(═O)(NR^(k))₂,—NR^(k)P(═O)(OR^(j))₂, —NR^(k)P(═O)(NR^(k))₂, —P(R^(j))₂, —P(R^(j))₃,—OP(R^(j))₂, —OP(R^(j))₃, —B(OR^(j))₂, —BR^(i)(OR^(j)), C₁₋₁₀ alkyl,C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₄ carbocyclyl,3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroaryl,wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl,and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5R^(m) groups;

each instance of R^(i) is, independently, selected from C₁₋₁₀ alkyl,C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocyclyl,3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroaryl,wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl,and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5R^(m) groups;

each instance of R^(k) is, independently, selected from hydrogen, —OH,—OR^(i), —N(R^(j))₂, —CN, —C(═O)R^(i), —C(═O)N(R^(j))₂, —CO₂R^(i),—SO₂R^(i), —C(═NR^(j))OR^(i), —C(═NR^(j))N(R^(j))₂, —SO₂N(R^(j))₂,—SO₂R^(j), —SO₂OR^(j), —SOR^(i), —C(═S)N(R^(j))₂, —C(═O)SR^(j),—C(═S)SR^(j), —P(═O)₂R^(i), —P(═O)(R^(i))₂, —P(═O)₂N(R^(j))₂,—P(═O)(NR^(i))₂, C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, C₃₋₁₀ carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and5-14 membered heteroaryl, or two R^(j) groups attached to an N atom arejoined to fo R^(m) a 3-14 membered heterocyclyl or 5-14 memberedheteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl,heterocyclyl, aryl, and heteroaryl is independently substituted with 0,1, 2, 3, 4, or 5 R^(m) groups;

each instance of is, independently, selected from hydrogen, C₁₋₁₀ alkyl,C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocyclyl,3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroaryl, ortwo R^(j) groups attached to an N atom are joined to form a 3-14membered heterocyclyl or 5-14 membered heteroaryl ring, wherein eachalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroarylis independently substituted with 0, 1, 2, 3, 4, or 5 R^(m) groups;

each instance of R^(m) is, independently, selected from fluoro (—F),bromo (—Br), chloro (—Cl), and iodo (—I), —CN, —NO₂, —N₃, —SO₂H, —SO₃H,—OH, —ORo, —ON(R^(n))₂, —N(R^(n))₂, —N(R^(n))₃ ⁺X⁻, —N(ORo)Rn, —SH,—SR^(o), —SSR^(o), —C(═O)R^(o), —CO₂H, —CO₂R^(o), —OC(═O)R^(o),—OCO₂R^(o), —C(═O)N(R^(n))₂, —OC(═O)N(R^(n))₂, —NRnC(═O)R^(o),—NR^(n)CO₂R^(o), —NR^(n)C(═O)N(R^(n))₂, —C(═NR^(n))OR^(o),—OC(═NR^(n))R^(o), —OC(═NR^(n))OR^(o), —C(═NR^(n))N(R^(n))₂,—OC(═NR^(n))N(R^(n))₂, —NR^(n)C(═NR^(n))N(R^(n))₂, —NR^(n)SO₂R^(o),—SO₂N(R^(n))₂, —SO₂R^(o), —SO₂OR^(o), —OSO₂R^(o), —S(═O)R^(o),—Si(R^(o))₃, —OSi(R^(o))₃, —C(═S)N(R^(n))₂, —C(═O)SR^(o), —C(═S)SR^(o),—SC(═S)SR^(o), —P(═O)₂R^(o), —P(═O)(R^(o))₂, —OP(═O)(R^(o))₂,—OP(═O)(OR^(o))₂, C₁₋₆ alkyl, C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, 5-14membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl,heterocyclyl, aryl, and heteroaryl is independently substituted with 0,1, 2, 3, 4, or 5 R^(p) groups, or two geminal R^(m) substituents can bejoined to form ═O or ═S;

each instance of R^(o) is, independently, selected from C₁₋₆ alkyl, C₁₋₆perhaloalkyl, C₂₋₆ alkenyl, C₂ alkynyl, C₃₋₁₀ carbocyclyl, C₆₋₁₀ aryl,3-10 membered heterocyclyl, and 3-10 membered heteroaryl, wherein eachalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroarylis independently substituted with 0, 1, 2, 3, 4, or 5 R^(p) groups;

each instance of R^(n) is, independently, selected from hydrogen, C₁₋₆alkyl, C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl,3-10 membered heterocyclyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl, ortwo R^(n) groups attached to an N atom are joined to form a 3-14membered heterocyclyl or 5-14 membered heteroaryl ring, wherein eachalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroarylis independently substituted with 0, 1, 2, 3, 4, or 5 R^(p) groups; and

each instance of R^(p) is, independently, fluoro (—F), bromo (—Br),chloro (—Cl), and iodo (—I), —CN, —NO₂, —SO₂H, —SO₃H, —OH, —OC₁₋₆ alkyl,—ON(C₁₋₆ alkyl)₂, alkyl)₂, alkyl)₃X, —NH(C₁₋₆ alkyl)₂X, —NH₂(C₁₋₆alkyl)X, —NH₃X, —N(OC₁₋₆ alkyl)(C₁₋₆ alkyl), —N(OH)(C₁₋₆ alkyl),—NH(OH), —SH, —SC_(is) alkyl, —SS(C₁₋₆ alkyl), —C(═O)(C₁₋₆ alkyl),—CO₂H, —CO₂ (C₁₋₆ alkyl), —OC(═O)(C₁₋₆ alkyl), —OCO₂ (C₁₋₆ alkyl),—C(═O)NH₂, —C(═O)N(C₁₋₆ alkyl)₂, —OC(═O)NH(C₁₋₆ alkyl), —NHC(═O)(C₁₋₆alkyl), —N(C₁₋₆ alkyl)C(═O)(C₁₋₆ alkyl), —NHCO₂(C₁₋₆ alkyl),—NHC(═O)N(C₁₋₆ alkyl)₂, —NHC(═O)NH(C₁₋₆ alkyl), —NHC(═O)NH₂,—C(═NH)O(C₁₋₆ alkyl), —OC(═NH)(C₁₋₆ alkyl), —OC(═NH)OC₁₋₆ alkyl,—C(═NH)N(C₁₋₆ alkyl)₂, —C(═NH)NH(C₁₋₆ alkyl), —C(═NH)NH₂, —OC(═NH)N(C₁₋₆alkyl)₂, —OC(NH)NH(C₁₋₆ alkyl), —OC(NH)NH₂—NHC(NH)N(C₁₋₆ alkyl)₂,—NHC(═NH)NH₂, SO₂ (C₁₋₆ alkyl), —SO₂N(C₁₋₆ alkyl)₂, —SO₂NH(C₁₋₆ alkyl),—SO₂NH₂, —SO₂C₁₋₆ alkyl, —SO₂OC₁₋₆ alkyl, —OSO₂C₁₋₆ alkyl, —SOC₁₋₆alkyl, —Si(C₁₋₆ alkyl)₃, —OSi(C₁₋₆ alkyl)₃ —C(═S)N(C₁₋₆ alkyl)₂,C(═S)NH(C₁₋₆ alkyl), C(═S)NH₂, —C(═O)S(C₁₋₆ alkyl), —C(═S)SC₁₋₆ alkyl,—SC(═S)SC₁₋₆ alkyl, —P(═O)₂(C₁₋₆ alkyl), —P(═O)(C₁₋₆ alkyl)₂,—OP(═O)(C₁₋₆ alkyl)₂, —OP(═O)(OC₁₋₆ alkyl)₂, C₁₋₆ alkyl, C₁₋₆perhaloalkyl, C₂₋₆ alkenyl, C₂ alkynyl, C₃₋₁₀ carbocyclyl, C₆₋₁₄ aryl,3-14 membered heterocyclyl, 5-14 membered heteroaryl; or two geminal Rpsubstituents can be joined to form ═O or ═S;

wherein X⁻ is a counterion.

In certain embodiments, R^(h) is selected from fluoro (—F), bromo (—Br),chloro (—Cl), and iodo (—I), —CN, —NO₂, —OH, —OR^(i), —SR^(i), —SO₂H,—SO₃H, —N(R^(k))₂, —N(R^(k))₃—C(═O)R^(i), —CO₂H, —CHO, —CO₂R^(i),—OC(═O)R^(i), —OCO₂R^(i), —C(═O)N(R^(k))₂, —OC(═O)N(R⁴)₂,—NR^(k)C(═O)R^(i), —NR^(k)CO₂R^(i), —NR^(k)C(═O)N(R^(k))₂,—C(═NR^(k))R^(i), —C(═NR^(k))OR^(i), —OC(═NR^(k))R^(i),—OC(═NR^(k))OR^(i), —C(═NR^(k))N(R^(k))₂, —OC(═NR^(k))N(R^(k))₂,—NR^(k)C(═NR^(k))N(R^(k))₂, —C(═O)NR^(k)SO₂R^(i), —NR^(k)SO₂R^(i),—SO₂N(R^(k))₂, —SO₂R^(i), —SO₂OR^(i), —OSO₂R^(i), —S(═O)R^(i),—OS(═O)R^(i), —C(═S)N(R^(k))₂, —C(═O)SR^(i), —C(═S)SR^(i), —SC(S)SR^(i),—P(═O)₂R^(i), —OP(═O)₂R^(i), —P(═O)(R^(i))₂, —OP(═O)(R^(i))₂,—OP(═O)(OR^(j))₂, —P(═O)₂N(R^(k))₂, —OP(═O)₂N(R^(k))₂, —P(═O)(NR^(k))₂,—OP(═O)(NR^(k))₂, —NR^(k)P(═O)(OR^(j))₂, —NR^(k)P(═O)(NR^(k))₂,—B(OR^(j))₂, —BR^(i)(OR^(j)), C₁₋₁₀ alkyl, —C₁₋₁₀ perhaloalkyl, C₃₋₁₄carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 memberedheteroaryl, wherein each alkyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^(m)groups; and wherein X⁻ is a counterion.

In certain embodiments, R^(h) is selected from fluoro (—F), bromo (—Br),chloro (—Cl), and iodo (—I), —CN, —NO₂, —OH, —OR^(i), —SR^(i),—N(R^(k))₂, —N(R^(k))₃—C(═O)R^(i), —CO₂R^(i), —CO₂H, —OC(═O)R^(i),—OCO₂R^(i), —C(═O)N(R^(k))₂, —OC(═O)N(R^(k))₂, —NR^(k)C(═O)R^(i),—NR^(k)CO₂R^(i), —NR^(k)C(═O)N(R^(k))₂, —C(═O)NR^(k)SO₂R^(i),—NR^(k)SO₂R^(i), —SO₂N(R^(k))₂, —SO₂R^(i), C₁₋₁₀ alkyl, C₆ aryl, and 5-6membered heteroaryl, wherein each alkyl, aryl, and heteroaryl isindependently substituted with 0, 1, 2, 3 or 4 R^(m) groups; and whereinX⁻ is a counterion.

In certain embodiments, R^(h) is —OR^(i), e.g., selected from —OCH₃,—OCF₃, —OCH₂CH₃, —OCH₂CF₃, —OiPr and —OnBu.

In certain embodiments, R^(h) is —SR^(i), e.g., selected from —SCH₃.

In certain embodiments, R^(h) is —N(R^(k))₂ or —N(R^(k))₃ ⁻X⁻, e.g.,selected from —NH₂ and —NH₃ ⁺X⁻.

In certain embodiments, R^(h) is —C(═O)R^(i), e.g., selected from—C(═O)CH₃.

In certain embodiments, R^(h) is —CO₂R^(i), e.g., selected from —CO₂CH₃

In certain embodiments, R^(h) is —C(═O)N(R^(k))₂, e.g., selected from—C(═O)NHOH, —C(═O)NH₂, —C(═O)NHCH₃, —C(═O)N(CH₃)₂, —C(═O)NHCH₂CH₃,—C(═O)NHCH₂CF₃—C(═O)NH(CH₂)₁₋₆NH₃—C(═O)NHCH₂C(═O)OCH₃,—C(═O)NHCH₂C(═O)OH and —C(═O)NHCH₂CH₂OH.

In certain embodiments, R^(h) is —OC(═O)R^(i), e.g., selected from—OC(═O)CH₃.

In certain embodiments, R^(h) is —OCO₂R^(i), e.g., selected from—OCO₂CH₃.

In certain embodiments, R^(h) is —OC(═O)N(R^(k))₂, e.g., selected from—OC(═O)NH₂.

In certain embodiments, R^(h) is —NR^(k)C(═O)R^(i), e.g., selected from—NHC(═O)CH₃.

In certain embodiments, R^(h) is —NR^(k)CO₂R^(i), e.g., selected from—NHC(═O)OCH₃ and —NHC(═O)OtBu.

In certain embodiments, R^(h) is —NR^(k)C(═O)N(R^(k))₂, e.g., selectedfrom NHC(═O)NH₂.

In certain embodiments, R^(h) is —C(═O)NR^(k)SO₂R^(i), e.g., selectedfrom —C(═O)NHSO₂CH₃, —C(═O)NHSO₂CH₂CH₃, —C(═O)NHSO₂C₅H₉ and—C(═O)NHSO₂₁Bu.

In certain embodiments, R^(h) is —NR^(k)SO₂R^(i), e.g., selected from—NHSO₂CH₃.

In certain embodiments, R^(h) is —SO₂N(R^(k))₂, e.g., selected from—SO₂NH₂₅—SO₂N(CH₃)₂.

In certain embodiments, R^(h) is —SO₂R^(i), e.g., selected from —SO₂CH₃,—SO₂CH₂CH₃, —SO₂C₅H₉ and —SO₂₁Bu.

In certain embodiments, R^(h) is C₁₋₁₀ alkyl, e.g., selected from —CH₃,—CH₂CH₃, -iPr, -nBu, —CF₃, —CH₂CH₂CO₂Me, —CH₂CH₂CO₂H and —CH₂CH₂CO₂NH₂.

In certain embodiments, R^(h) is selected from —C(═O)R^(i), —CO₂H, and—SO₂R^(i). In certain embodiments, R^(h) is —C(═O)R^(i). In certainembodiments, R^(h) is —SO₂R^(i). In certain embodiments, R^(h) is —CO₂Hor —SO₂CH₃. In certain embodiments, R^(h) is —CO₂H. In certainembodiments, R^(h) is —SO₂CH₃.

In certain embodiments, each instance of R^(h) is, independently,selected from fluoro (—F), bromo (—Br), chloro (—Cl), iodo (—I), —NH₂,—CN, —NO₂, —SO₂CH₃—SO₂CH₂CH₃, —SO₂C₅H₉, —SO₂₁Bu, —SO₂NH₂, —SO₂N(CH₃)₂,—C(—O)NHSO₂CH₃, —C(═O)NHSO₂CH₂CH₃, —C(═O)NHSO₂C₅H₉, —C(═O)NHSO₂₁Bu,—C(═O)CH₃, —CO₂H, —CO₂CH₃, —OC(═O)CH₃, —OCO₂CH₃, —C(═O)NHOH, —C(═O)NH₂,—C(═O)NHCH₃—C(═O)N(CH₃)₂, —C(═O)NHCH₂CH₃,—C(═O)NHCH₂CF₃—C(═O)NH(CH₂)₁₆NH₃—OC(O)NH₂, —NHC(═O)CH₃, —NHC(═O)OCH₃,—NHC(═O)OtBu, —NHC(═O)NH₂, —NHSO₂CH₃—CH₃, —CH₂CH₃, -iPr, -nBu, —CF₃,—OH, —OCH₃, —SCH₃, —OCF₃, —OCH₂CH₃, —OCH₂CF₃, —OiPr, —OnBu,—CH₂CH₂CO₂Me, —CH₂CH₂CO₂H, —CH₂CH₂CO₂NH₂, —C(═O)NHCH₂C(═O)OCH₃,—C(═O)NHCH₂C(═O)OH, —C(═O)NHCH₂CH₂OH, C₆ aryl substituted with 0, 1, or2 R^(m) groups and 5-6 membered heteroaryl substituted with 0, 1, or 2R^(m) groups; and wherein X⁻ is a counterion.

In certain embodiments, R^(h) is a C₆ aryl (e.g., phenyl) substitutedwith 0, 1, or 2 R^(m) groups. In certain embodiments, R^(h) is a C₆ aryl(e.g., phenyl) substituted with 1 R^(m) group, and R^(m) is —CO₂H,—CO₂CH₃, —CO₂CH₂CH₃, and —C(═O)NH₂.

In certain embodiments, R^(h) is a 5-6 membered heteroaryl substitutedwith 0, 1, or 2 R^(m) groups. In certain embodiments, R^(h) is a 5membered heteroaryl substituted with 0, 1, or 2 R^(m) groups. Exemplary5 membered heteroaryl R^(h) groups include, but are not limited to,pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl,thiadiazolyl, and tetrazolyl, wherein such groups are substituted with 0or 1 R^(m) groups. In certain embodiments, the R^(h) 5 memberedheteroaryl group is selected from pyrazolyl and oxadiazolyl, whereinsuch groups are substituted with 0 or 1 R^(m) groups.

Embodiments of R^(i)

In certain embodiments, each instance of R^(i) is, independently,selected from C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, C₃₋₁₀ carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and5-14 membered heteroaryl, wherein each alkyl, carbocyclyl, heterocyclyl,aryl, and heteroaryl is unsubstituted.

In certain embodiments, R^(i) is unsubstituted C₁₋₁₀ alkyl. In certainembodiments, R^(i) is C₁₋₁₀ perhaloalkyl. In certain embodiments, R^(i)is unsubstituted C₂₋₁₀ alkenyl. In certain embodiments, R^(i) isunsubstituted C₂₋₁₀ alkynyl. In certain embodiments, R^(i) isunsubstituted C₃₋₁₀ carbocyclyl. In certain embodiments, R^(i) isunsubstituted 3-14 membered heterocyclyl. In certain embodiments, R^(i)is unsubstituted C₆₋₁₄ aryl. In certain embodiments, R^(i) isunsubstituted 5-14 membered heteroaryl.

Embodiments of R^(m)

In certain embodiments, each instance of R^(m) is, independently,selected from fluoro (—F), bromo (—Br), chloro (—Cl), and iodo (—I),—CN, —NO₂, —SO₂H, —SO₃H, —OH, —OR^(o), —ON(R^(n))₂, —N(R^(n))₂,—N(R^(n))₃₊X⁻, —N(OR^(o)R^(n), —SH, —SR^(o), —SSR^(o), —C(═O)R^(o),—CO₂H, —CO₂R^(o), —OC(═O)R^(o), —OCO₂R^(o), —C(═O)N(R^(n))₂,—OC(═O)N(R^(n))₂, —NR^(n)(═O)R^(o), —NR^(n)CO₂R^(o),—NR^(n)(═O)N(R^(n))₂, —C(═NR)OR^(o), —OC(═NR^(n))R^(o),—OC(═NR^(n))OR^(o), —C(═NR^(n))N(R^(n))₂, —OC(═NR^(n))N(R^(n))₂,—NR^(n)C(═NR^(n))N(R^(n))₂, —NR^(n)SO₂R^(o), —SO₂N(R^(n))₂, —SO₂R^(o),—SO₂OR^(o), —OSO₂R^(o), —S(═O)R^(o), —C(═S)N(R^(n))₂, —C(═O)SR^(o),—C(═S)SR^(o), —SC(═S)SR^(o), —P(═O)₂R^(o), —P(═O)(R^(o)O₂,—OP(═O)(R^(o))₂, —OP(═O)(ORO₂, C₁₋₆ alkyl, C₁₋₆ perhaloalkyl, C₃₋₁₀carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, 5-14 memberedheteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl,heterocyclyl, aryl, and heteroaryl is independently substituted with 0,1, 2, 3, 4, or 5 R^(p) groups.

In certain embodiments, each instance of R^(m) is, independently,selected from fluoro (—F), bromo (—Br), chloro (—Cl), and iodo (—I),—CN, —NO₂, —SO₂H, —SO₃H, —OH, —OR^(o), —ON(R^(n))₂, —N(R^(n))₂,—N(R^(n))₃ ⁺X⁻, —N(OR^(o))R^(n), —SH, —SR^(o), —SSR^(o), —C(═O)R^(o),—CO₂H, —CO₂R^(o), —OC(═O)R^(o), —OCO₂R^(o), —C(═O)N(R^(n))₂,—OC(═O)N(R^(n))₂, —NR^(n)C(═O)R^(o), —NR^(n)CO₂R^(o),—NR^(n)C(═O)N(R^(n))₂, —C(═NR^(n))OR^(o), —OC(═NR^(n))R^(o),—OC(═NR^(n))OR^(o), —C(═NR^(n))N(R^(n))₂, —OC(═NR^(n))N(R^(n))₂,—NR^(n)C(═NR^(n))N(R^(n))₂, —NR^(n)SO₂R^(o), —SO₂N(R^(n))₂, —SO₂R^(o),—SO₂OR^(o), —OSO₂R^(o), —S(═O)R^(o), —C(═S)N(R^(n))₂, —C(═O)SR^(o),—C(═S)SR^(o), —SC(═S)SR^(o), —P(═O)₂R^(o), —P(═O)(R^(o))₂,—OP(═O)(R^(o))₂, —OP(═O)(OR^(o))₂, C₁₋₆ alkyl, C₁₋₆ perhaloalkyl, C₃₋₁₀carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, 5-14 memberedheteroaryl.

In certain embodiments, R^(m) is selected from fluoro (—F), bromo (—Br),chloro (—Cl), and iodo (—I), —NH₂, —CN, —NO₂, —SO₂CH₃, —SO₂CH₂CH₃,—SO₂C₅H₉, —SO₂₁Bu, —SO₂NH₂, —SO₂N(CH₃)₂, —C(═O)NHSO₂CH₃,—C(═O)NHSO₂CH₂CH₃, —C(═O)NHSO₂C₅H₉, —C(═O)NHSO₂₁Bu, —C(═O)CH₃, —CO₂H,—CO₂CH₃, —OC(═O)CH₃, —OCO₂CH₃, —C(═O)NHOH, —C(═O)NH₂, —C(═O)NHCH₃,—C(═O)N(CH₃)₂, —C(═O)NHCH₂CH₃,—C(═O)NHCH₂CF₃—C(═O)NH(CH₂)₁₋₆NH₃—OC(O)NH₂, —NHC(═O)CH₃, —NHC(═O)OCH₃,—NHC(═O)OtBu, —NHC(═O)NH₂, —NHSO₂CH₃, —CH₃, —CH₂CH₃, -iPr, -nBu, —CF₃,—OH, —OCH₃, —OCF₃, —OCH₂CH₃, —OCH₂CF₃, —OiPr, —OnBu, —CH₂CH₂CO₂Me,—CH₂CH₂CO₂H, —CH₂CH₂CO₂NH₂, —C(═O)NHCH₂C(═O)OCH₃, —C(═O)NHCH₂C(═O)OH,and —C(═O)NHCH₂CH₂OH.

Embodiments of R^(k)

As used above and herein each instance of R^(k) is, independently,selected from —H, —OH, —OR^(i), —N(R^(k))₂, —C(═O)R^(i),—C(═O)N(R^(k))₂, —CO₂R^(i), —SO₂R^(i), —C(═NR^(k))R^(i),—C(═NR^(k))OR^(i), —C(═NR^(k))N(R^(k))₂, —SO₂N(R^(k))₂, —SO₂R^(i),—SO₂OR^(i), —SOR^(i), —C(═S)N(R^(k))₂, —C(═O)SR^(i), —C(═S)SR^(i), C₁₋₁₀alkyl (e.g., aralkyl), C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocyclyl,3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroarylgroups, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl,aralkyl, aryl, and heteroaryl is independently substituted with 0, 1, 2,3, 4, or 5 R^(m) groups, wherein R^(k), R^(m) are as defined above andherein.

In certain embodiments, each instance of R^(k) is, independently,selected from —H, —C(═O)R^(i), —C(═O)OR^(i), —SO₂R^(i), or C₁₋₆ alkyl.In certain embodiments, each instance of R^(k) is, independently,selected from —H or C₁₋₆ alkyl. In certain embodiments, each instance ofR^(k) is, independently, selected from —H and —CH₃. In certainembodiments, each instance of R^(k) is, independently, selected from —H.In certain embodiments, each instance of R^(k) is, independently,selected from —CH₃.

Groups R^(a), R^(b), and R^(c)

As generally defined above, wherein R^(d) is the group -L-Z, each ofR^(a), R^(b), and R^(c) independently is selected from —H, C₁₋₁₀ alkyland C₁₋₁₀ perhaloalkyl.

In certain embodiments, each of R^(a), R^(b), and R^(c) independently isselected from —H, C₁₋₆ alkyl and C₁₋₆ perhaloalkyl. In certainembodiments, each of R^(a), R^(b), and R^(c) independently is selectedfrom —H, C₁₋₃ alkyl and C₁₋₃ perhaloalkyl. In certain embodiments, eachof R^(a), R^(b), and R^(c) independently is selected from —H, —CH₃,—CH₂CH₃ and —CF₃. In certain embodiments, each of R^(a), R^(b), andR^(c) independently is selected from —H, —CH₃, and —CF₃.

In certain embodiments, R^(a) and R^(b) are H and R^(c) is selected fromC₁₋₃ alkyl and C₁₋₃ perhaloalkyl. In certain embodiments, R^(a) andR^(b) are H and R^(c) is selected from —CH₃ and —CF₃. In certainembodiments, R^(a) and R^(b) are H and R^(c) is —CH₃. In certainembodiments, R^(a) and R^(b) are H and R^(c) is —CF₃.

In certain embodiments, R^(b) and R^(c) are H and R^(a) is selected fromC₁₋₃ alkyl and C₁₋₃ perhaloalkyl. In certain embodiments, R^(b) andR^(c) are H and R^(a) is selected from —CH₃ and —CF₃. In certainembodiments, R^(b) and R^(c) are H and R^(a) is —CH₃. In certainembodiments, R^(b) and R^(c) are H and R^(a) is —CF₃.

In certain embodiments, each of R^(a), R^(b), and R^(c) independently isselected from H, —CH₃ and —CF₃. In certain embodiments, each of R^(a),R^(b), and R^(c) independently is selected from H or —CH₃. In certainembodiments, each of R^(a), R^(b), and R^(c) is H.

Group R^(d)

As generally defined above, in certain embodiments, R^(d) is the group-L-Z,

wherein L is a covalent bond or a divalent C₁₋₆ hydrocarbon group,wherein one, two or three methylene units of L are optionally andindependently replaced with one or more oxygen, sulfur or nitrogenatoms, and Z is selected from 3-14 membered heterocyclyl or 5-14membered heteroaryl.

Group L of R^(d)

As generally defined above, L is a covalent bond or a divalent C₁hydrocarbon group, wherein one, two or three methylene units of L areoptionally and independently replaced with one or more oxygen, sulfur ornitrogen atoms.

In certain embodiments, L is a covalent bond.

In certain embodiments, L is a divalent C₁ hydrocarbon group, whereinone, two or three methylene units of L are optionally and independentlyreplaced with one or more oxygen (—O—), sulfur (—S—) or nitrogen (e.g.,—NR¹—) atoms.

In certain embodiments, L is a divalent C₁ hydrocarbon group, whereinone, two or three methylene units of L are optionally and independentlyreplaced with one or more oxygen (—O—) atoms.

In certain embodiments, L is a divalent C₁ hydrocarbon group, whereinone, two or three methylene units of L are optionally and independentlyreplaced with one or more sulfur (—S—) atoms.

In certain embodiments, L is a divalent C₁ hydrocarbon group, whereinone, two or three methylene units of L are optionally and independentlyreplaced with one or more nitrogen (—NR¹—) atoms. However, in certainembodiments, wherein L is a divalent C₁₋₆ hydrocarbon group comprisingone, two or three nitrogen atoms, then L is an unsubstituted divalentC₁₋₆ hydrocarbon group and L is not the group —CH₂NR¹— wherein R¹ is H,C₁₋₆ alkyl or an amino protecting group.

In certain embodiments, L is a divalent C₁₋₆ hydrocarbon group, whereinone methylene unit of L is optionally and independently replaced with anoxygen, sulfur or nitrogen atom. In certain embodiments, L is a divalentC₁₋₆ hydrocarbon group, wherein one methylene unit of L is optionallyand independently replaced with an oxygen atom. In certain embodiments,L is a divalent C₁ hydrocarbon group, wherein one methylene unit of L isoptionally and independently replaced with a sulfur atom. In certainembodiments, L is a divalent C_(is) hydrocarbon group, wherein onemethylene unit of L is optionally and independently replaced with anitrogen atom.

In certain embodiments of L, the divalent C₁₋₆ hydrocarbon group is anunsubstituted divalent C₁ hydrocarbon group. In certain embodiments ofL, the divalent C₁₋₆ hydrocarbon group contains one oxygen, sulfur ornitrogen atom. In certain embodiments, the divalent C₁₋₆ hydrocarbongroup is an unsubstituted divalent C₁₋₆ hydrocarbon group (e.g., anunsubstituted divalent C₁₋₆ alkyl group).

For example, in certain embodiments, L is an unsubstituted divalent C₁₋₆alkyl group, wherein one methylene unit of L is replaced with an oxygen,sulfur or nitrogen atom. In certain embodiments, L is an unsubstituteddivalent C₁₋₆ alkyl group, wherein one methylene unit of L is replacedwith an oxygen atom. In certain embodiments, L is an unsubstituteddivalent C₁₋₆ alkyl, wherein one methylene unit of L is replaced with asulfur atom. In certain embodiments, L is an unsubstituted divalent C₁₋₆alkyl group, wherein one methylene unit of L is replaced with a nitrogenatom. However, in certain embodiments, wherein L is an unsubstituteddivalent C₁₋₆ alkyl group, then L is not the group —CH₂NR¹— wherein R¹is H, C₁₋₆ alkyl or an amino protecting group.

In certain embodiments, L is a divalent C₁ hydrocarbon group, whereinone methylene unit of L is replaced with an oxygen, sulfur or nitrogenatom, e.g., L is selected from oxygen (—O—), sulfur (—S—) or nitrogen(e.g., —NR¹—). In certain embodiments, L is oxygen (—O—). In certainembodiments, L is sulfur (—S—). In certain embodiments, L is nitrogen(e.g., —NR¹—).

In certain embodiments, L is selected from the group consisting of—(C(R¹⁰)₂)_(m)—, —(C(R¹¹)₂)_(m)—O—(C(R¹²)₂)_(n)—, or—(C(R¹¹)_(m)—S—(C(R¹²)₂)_(n)—, —(C(R¹¹)₂)_(m)—NR¹—(C(R¹²)₂)_(n)—,wherein m and n are, independently, 0, 1, 2, 3, 4, 5 or 6, and eachinstance of R¹⁰, R¹¹ and R¹² are, independently, selected from H,halogen or C₁₋₆ alkyl. In certain embodiments, each of R¹⁰, R¹¹ and R¹²are —H.

In certain embodiments, L is —(C(R¹⁰)₂)_(m)—. In certain embodiments, Lis selected from —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂—,—CH₂CH₂CH₂CH₂CH₂— and —CH₂CH₂CH₂CH₂CH₂CH₂—.

In certain embodiments, L is —(C(R^(n))₂)_(m)—O—(C(R¹²)₂)_(n)—. Incertain embodiments, L is selected from —O—, —CH₂O—, —OCH₂—,—OCH₂CH₂₋₅—OCH₂CH₂—, —OCH₂CH₂CH₂—, —CH₂CH₂CH₂O—, —CH₂OCH₂CH₂—, and—CH₂CH₂OCH₂—.

In certain embodiments, L is —(C(R^(n))₂)_(m)—S—(C(R¹²)₂)_(n)—. Incertain embodiments, L is selected from —S—, —CH₂S—, —SCH₂—,—SCH₂CH₂₋₅—CH₂CH₂S—, —SCH₂CH₂CH₂—, —CH₂CH₂CH₂S—, —CH₂SCH₂CH₂—, and—CH₂CH₂SCH₂—.

In certain embodiments, L is —(C(R¹¹)₂)_(m)—NR¹—(C(R¹²)₂)_(n)—. Incertain embodiments, L is selected from —NR¹—, —CH₂NR¹—, —NR¹CH₂—,—NR¹CH₂CH₂—, —CH₂CH₂NR¹—, —NR¹CH₂CH₂CH₂—, —CH₂CH₂CH₂NR¹—,—CH₂NR¹CH₂CH₂—, and —CH₂CH₂NR¹CH₂—, wherein R¹ is selected from H, anC₁₋₆ alkyl or an amino protecting group.

In certain embodiments, R¹ is selected from H or C₁₋₆ alkyl. In certainembodiments, R¹ is hydrogen. In certain embodiments, R¹ is —CH₃.

Group Z of R^(d)

As generally defined above, Z is selected from 3-14 membered heterocycyland 5-14 membered heteroaryl.

In certain embodiments, Z is 5-14 membered heteroaryl. In certainembodiments, Z is a 5-10 membered heteroaryl substituted with 0, 1, 2,3, 4 or 5 R¹⁵ groups. In certain embodiments, Z is a 5-8 memberedheteroaryl substituted with 0, 1, 2, 3, 4 or 5 R¹⁵ groups. In certainembodiments, Z is a 5-6 membered heteroaryl substituted with 0, 1, 2, 3or 4 R¹⁵ groups. In certain embodiments, Z is a 9-10 membered heteroarylsubstituted with 0, 1, 2, 3, 4 or 5 R¹⁵ groups.

Exemplary Z heteroaryl groups include, but are not limited to, pyrrolyl,furanyl and thiophenyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl,thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl,tetrazolyl, pyridinyl (e.g., 2-pyridinyl, 3-pyridinyl, 4-pyridinyl),pyridazinyl (e.g., 3-pyridazinyl, 4-pyridazinyl), pyrimidinyl (e.g.2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyrazinyl, triazinyl,tetrazinyl, azepinyl, oxepinyl, thiepinyl, indolyl, isoindolyl,indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl,benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl,benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl,benzthiadiazolyl, indolizinyl, purinyl, naphthyridinyl, pteridinyl,quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl,quinazolinyl, phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl,phenothiazinyl, phenoxazinyl and phenazinyl, wherein such groups aresubstituted with 0, 1, 2, 3, 4 or 5 R¹⁵ groups.

In certain embodiments, Z is a 5-membered heteroaryl substituted with 0,1, 2 or 3 R¹⁵ groups. In certain embodiments, Z is a 5-memberedheteroaryl selected pyrrolyl, furanyl, thiophenyl, imidazolyl,pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl,oxadiazolyl, thiadiazolyl and tetrazolyl, wherein such groups aresubstituted with 0, 1, 2 or 3 R¹⁵ groups.

For example, in certain embodiments, Z is a 5-membered heteroaryl of theformula:

wherein Y¹, Y², Y³ and Y⁴ are, independently, selected from CH, CR¹⁵, O,S, N, or NR¹⁸, with the proviso that at least one of Y¹, Y², Y³ and Y⁴are selected from O, S, N, or NR¹⁸, and wherein R¹⁵ and R¹⁸ are definedbelow and herein.

In certain embodiments of the above formula (ii-d), Y¹ is O, S, or NR¹⁸and Y², Y³ and Y⁴ are, independently, selected from CH, CR¹⁵ or N. Incertain embodiments of the above formula (ii-d), Y¹ is O, S, or NR¹⁸ andY², Y³ and Y⁴ are, independently, selected from CH or CR¹⁵. In certainembodiments of the above formula (ii-d), Y¹ is O, S, or NR¹⁸, Y³ is Nand Y² and Y⁴ are, independently, selected from CH or CR¹⁵. In certainembodiments of the above formula (ii-d), Y¹ is S, Y³ is N, and Y² and Y⁴is CH or CR¹⁵. In certain embodiments of the above formula (ii-d), Y¹ isS, Y³ is N, Y² is CR¹⁵ and Y⁴ is CH. In certain embodiments of the aboveformula (ii-d), Y¹ is S and Y², Y³ and Y⁴ is CH or CR¹⁵.

In certain embodiments of the above formula (ii-d), Y² is O, S, or NR¹⁸and Y¹, Y³ and Y⁴ are, independently, selected from CH, CR¹⁵ or N. Incertain embodiments of the above formula (ii-d), Y² is O, S, or NR¹⁸ andY¹, Y³ and Y⁴ are, independently, selected from CH or CR¹⁵. In certainembodiments of the above formula (ii-d), Y² is O, S, or NR¹⁸, Y⁴ is Nand Y¹ and Y³ are, independently, selected from CH or CR¹⁵.

In certain embodiments, Z is a 5-membered heteroaryl of any one of theformulae:

wherein R¹⁵ and R¹⁸ are as defined below and herein, and z is 0, 1 or 2.

wherein z is 0, 1 or 2, and R¹⁵ and R¹⁸ are as defined below and herein.In certain embodiments, Z is an unsubstituted 5-membered heteroaryl(i.e., wherein z is 0). In certain embodiments, Z is a substituted5-membered heteroaryl (e.g., wherein z is 1 or 2). In certainembodiments, Z is a monosubstituted 5-membered heteroaryl (i.e., whereinz is 1). In certain embodiments, Z is a disubstituted 5-memberedheteroaryl (i.e., wherein z is 2). In certain embodiments, z is 0, 1 or2. In certain embodiments, z is 0 or 1.

In certain embodiments, Z is a 6-membered heteroaryl substituted with 0,1, 2, 3 or 4 R^(h) groups. In certain embodiments, Z is a 6-memberedheteroaryl selected from the group consisting of pyridinyl (e.g.,2-pyridinyl, 3-pyridinyl, 4-pyridinyl), pyridazinyl (e.g.,3-pyridazinyl, 4-pyridazinyl), pyrimidinyl (e.g. 2-pyrimidinyl,4-pyrimidinyl, 5-pyrimidinyl), pyrazinyl, triazinyl and tetrazinyl,wherein such groups are substituted with 0, 1, 2, 3 or 4 R¹⁵ groups.

For example, in certain embodiments, R^(e) is a 6-membered heteroarylgroup of the formula:

wherein W¹, W², W³, W⁴ and W⁵ are, independently, selected from CH, CR¹⁵or N, with the proviso that at least one of W¹, W², W³, W⁴, and W⁵ is N,and wherein R¹⁵ is as defined below and herein.

In certain embodiments, Z is a pyrindinyl group. In certain embodiments,Z is a pyrindinyl group substituted with 0, 1, 2, 3 or 4 R¹⁵ groups. Forexample, in certain embodiments, Z is a pyrindinyl group of the formula:

wherein z is 0, 1, 2, 3 or 4, and R¹⁵ is as defined below and herein. Incertain embodiments, Z is an unsubstituted pyrindinyl (i.e., wherein zis 0). In certain embodiments, Z is a substituted pyrindinyl (e.g.,wherein z is 1, 2, 3 or 4). In certain embodiments, Z is amonosubstituted pyrindinyl (i.e., wherein z is 1). In certainembodiments, Z is a disubstituted pyrindinyl (i.e., wherein z is 2). Incertain embodiments, Z is a trisubstituted pyrindinyl (i.e., wherein zis 3). In certain embodiments, z is 0, 1, 2 or 3. In certainembodiments, z is 0, 1 or 2. In certain embodiments, z is 0 or 1.

In certain embodiments, Z is a 2-pyrindinyl group, e.g., of the formula(ii-e) wherein W¹ is N and W², W³, W⁴ and W⁵ are, independently, CH orCR¹⁵. In certain embodiments Z is a 3-pyrindinyl group, e.g., of theformula (ii-e) wherein W² is N and W¹, W³, W⁴ and W⁵ are, independently,CH or CR¹⁵. In certain embodiments Z is a 4-pyrindinyl group, e.g., ofthe formula (ii-e) wherein W³ is N and W¹, W², W⁴ and W⁵ are,independently, CH or CR¹⁵.

In certain embodiments, R^(e) is a substituted or unsubstituted2-pyridinyl group of any one of the formulae:

wherein R¹⁵ is defined below and herein.

In certain embodiments, Z is a substituted or unsubstituted 3-pyridinylgroup of any one of the formulae:

wherein R¹⁵ is as defined below and herein.

In certain embodiments, Z is a substituted or unsubstituted 4-pyridinylgroup of the formulae:

wherein R¹⁵ is as defined below and herein.

In certain embodiments, Z is a pyridazinyl group. In certainembodiments, Z is a pyridazinyl group substituted with 0, 1, 2 or 3 R¹⁵groups. For example, in certain embodiments, Z is a pyridazinyl group ofthe formula:

wherein z is 0, 1, 2 or 3, and R¹⁵ is as defined below and herein. Incertain embodiments, Z is an unsubstituted pyridazinyl (i.e., wherein zis 0). In certain embodiments, Z is a substituted pyridazinyl (e.g.,wherein z is 1, 2 or 3). In certain embodiments, Z is a monosubstitutedpyridazinyl (i.e., wherein z is 1). In certain embodiments, Z is adisubstituted pyridazinyl (i.e., wherein z is 2). In certainembodiments, Z is a trisubstituted pyridazinyl (i.e., wherein z is 3).In certain embodiments, z is 0, 1, 2 or 3. In certain embodiments, z is0, 1 or 2. In certain embodiments, z is 0 or 1.

In certain embodiments, Z is a 3-pyridazinyl group, e.g., of the formula(ii-e) wherein W¹ and W² are N and W³, W⁴ and W⁵ are, independently, CHor CR¹⁵. In certain embodiments Z is a 4-pyridazinyl group, e.g., of theformula (ii-e) wherein W² and W³ are N and W¹, W⁴ and W⁵ are,independently, CH or CR^(h).

In certain embodiments, Z is a substituted or unsubstituted3-pyridazinyl group of any one of the formulae:

wherein R¹⁵ is as defined below and herein.

In certain embodiments, Z is a substituted or unsubstituted4-pyridazinyl group of any one of the formulae:

wherein R¹⁵ is as defined below and herein.

In certain embodiments, Z is a pyrimidinyl group. In certainembodiments, Z is a pyrimidinyl group substituted with 0, 1, 2 or 3 R¹⁵groups. For example, in certain embodiments, Z is a pyrimidinyl group ofthe formula:

wherein z is 0, 1, 2 or 3, and R¹⁵ is as defined below and herein. Incertain embodiments, Z is an unsubstituted pyrimidinyl (i.e., wherein zis 0). In certain embodiments, Z is a substituted pyrimidinyl (e.g.,wherein z is 1, 2 or 3). In certain embodiments, Z is a monosubstitutedpyrimidinyl (i.e., wherein z is 1). In certain embodiments, Z is adisubstituted pyridazinyl (i.e., wherein z is 2). In certainembodiments, Z is a trisubstituted pyrimidinyl (i.e., wherein z is 3).In certain embodiments, z is 0, 1, 2 or 3. In certain embodiments, z is0, 1 or 2. In certain embodiments, z is 0 or 1.

In certain embodiments, Z is a 2-pyrimidinyl group, e.g., of the formula(ii-e) wherein W¹ and W⁵ are N and W², W³ and W⁴ are, independently, CHor CR¹⁵. In certain embodiments Z is a 4-pyrimidinyl group, e.g., of theformula (ii-e) wherein W¹ and W³ are N and W², W⁴ and W⁵ are,independently, CH or CR¹⁵. In certain embodiments Z is a 5-pyrimidinylgroup, e.g., of the formula (ii-e) wherein W² and W⁴ are N and W¹, W³and W⁵ are, independently, CH or CR¹⁵.

In certain embodiments, Z is a 2-pyrimidinyl group of any one of theformulae:

wherein R¹⁵ is as defined below and herein.

In certain embodiments, R^(e) is a 4-pyrimidinyl group of any one of theformulae:

wherein R¹⁵ is as defined below and herein.

In certain embodiments, Z is a 5-pyrimidinyl group of any one of theformulae:

wherein R¹⁵ is as defined below and herein.

In certain embodiments, Z is a pyrazinyl group. In certain embodiments,Z is a pyrazinyl group substituted with 0, 1, 2 or 3 R¹⁵ groups. Forexample, in certain embodiments, Z is a pyrazinyl group of the formula:

wherein z is 0, 1, 2 or 3, and R¹⁵ is as defined below and herein. Incertain embodiments, Z is an unsubstituted pyrazinyl (i.e., wherein z is0). In certain embodiments, Z is a substituted pyrazinyl (e.g., whereinz is 1, 2 or 3). In certain embodiments, Z is a monosubstitutedpyrazinyl (i.e., wherein z is 1). In certain embodiments, Z is adisubstituted pyrazinyl (i.e., wherein z is 2). In certain embodiments,Z is a trisubstituted pyrazinyl (i.e., wherein z is 3). In certainembodiments, z is 0, 1, 2 or 3. In certain embodiments, z is 0, 1 or 2.In certain embodiments, z is 0 or 1.

In certain embodiments, Z is a pyrazinyl group of any one of theformulae:

wherein R¹⁵ is as defined below and herein.

In certain embodiments, Z is a triazinyl group. In certain embodiments,Z is a triazinyl group substituted with 0, 1 or 2 R¹⁵ groups. Forexample, in certain embodiments, Z is a triazinyl group of the formula:

wherein z is 0, 1 or 2, and R¹⁵ is as defined below and herein. Incertain embodiments, Z is an unsubstituted pyrazinyl (i.e., wherein z is0). In certain embodiments, Z is a substituted pyrazinyl (e.g., whereinz is 1 or 2). In certain embodiments, Z is a monosubstituted pyrazinyl(i.e., wherein z is 1). In certain embodiments, Z is a disubstitutedpyrazinyl (i.e., wherein z is 2). In certain embodiments, z is 0, 1 or2. In certain embodiments, z is 0 or 1.

In certain embodiments, Z is a substituted or unsubstituted triazinylgroup of any one of the formulae:

wherein R¹⁵ is as defined below and herein.

In certain embodiments Z is a tetrazinyl group. In certain embodiments Zis a tetrazinyl group substituted with 0 or 1 R¹⁵ groups. For example,in certain embodiments, Z is a tetrazinyl group of the formula:

wherein z is 0 or 1, and R¹⁵ is as defined below and herein. In certainembodiments, Z is an unsubstituted pyrazinyl (i.e., wherein z is 0). Incertain embodiments, Z is a substituted pyrazinyl (e.g., wherein z is1). In certain embodiments, z is 0 or 1.

In certain embodiments, Z is a tetrazinyl group of any one of theformulae:

wherein R¹⁵ is as defined below and herein.

In certain embodiments, Z is a 9-membered heteroaryl (e.g., a5,6-bicyclic heteroaryl). In certain embodiments, Z is a 5,6-bicyclicheteroaryl substituted with 0, 1, 2, 3, 4 or 5 R¹⁵ groups. In certainembodiments, Z is a 5,6-bicyclic heteroaryl selected from indolyl,isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl,isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl,benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl,benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl, whereinsuch groups are substituted with 0, 1, 2, 3, 4 or 5 R¹⁵ groups.

For example, in certain embodiments, Z is a 5,6-bicyclic heteroaryl ofthe formula:

wherein Y⁵, Y⁶, Y⁷, Y⁹, Y¹⁰, Y¹¹ and Y¹² are independently, C, CH, CR¹⁵,O, S, N, or NR¹⁸, and Y¹³ is C or N, with the proviso that at least oneof Y⁵, Y⁶, Y⁷ are selected from O, S, N or NR¹⁸, and wherein R¹⁵ and R¹⁸are as defined herein.

In certain embodiments, Z is a 5,6-bicyclic heteroaryl group of theformula wherein Y⁵ is selected from O, S, or NR¹⁸, Y¹³ is C, and Y⁶, Y⁷,Y⁹, Y¹⁰, Y¹¹ and Y¹² are, independently, C, CH, or CR¹⁵. For example, incertain embodiments, Z is a 5,6-bicyclic heteroaryl group of theformulae:

wherein z is 0, 1, 2, 3, 4 or 5 and R¹⁵ and R¹⁸ are defined below andherein. In certain embodiments, Z is an unsubstituted 5,6-bicyclicheteroaryl (i.e., wherein z is 0). In certain embodiments, Z is asubstituted 5,6-bicyclic heteroaryl (e.g., wherein z is 1, 2, 3, 4 or5). In certain embodiments, Z is a monosubstituted 5,6-bicyclicheteroaryl (i.e., wherein z is 1). In certain embodiments, Z is adisubstituted 5,6-bicyclic heteroaryl (i.e., wherein z is 2). In certainembodiments, Z is a trisubstituted 5,6-bicyclic heteroaryl (i.e.,wherein z is 3). In certain embodiments, z is 0, 1, 2 or 3. In certainembodiments, z is 0, 1 or 2. In certain embodiments, z is 0 or 1.

In certain embodiments, Z is a 5,6-bicyclic heteroaryl wherein Y⁵ isselected from O, S, or NR¹⁸; Y⁷ is N; Y¹³ is C; Y⁶ is C, CH, or CR¹⁵ orN, and Y⁹, Y¹⁰, Y¹¹ and Y¹² are, independently, C, CH, or CR¹⁵. Forexample, in certain embodiments, Z is a 5,6-bicyclic heteroaryl group ofthe formulae:

wherein z is 0, 1, 2, 3, 4 or 5 and R¹⁵ and R¹⁸ are defined below andherein. In certain embodiments, Z is an unsubstituted 5,6-bicyclicheteroaryl (i.e., wherein z is 0). In certain embodiments, Z is asubstituted 5,6-bicyclic heteroaryl (e.g., wherein z is 1, 2, 3, 4 or5). In certain embodiments, Z is a monosubstituted 5,6-bicyclicheteroaryl (i.e., wherein z is 1). In certain embodiments, Z is adisubstituted 5,6-bicyclic heteroaryl (i.e., wherein z is 2). In certainembodiments, Z is a trisubstituted 5,6-bicyclic heteroaryl (i.e.,wherein z is 3). In certain embodiments, z is 0, 1, 2 or 3. In certainembodiments, z is 0, 1 or 2. In certain embodiments, z is 0 or 1.

In certain embodiments, Z is a 5,6-bicyclic heteroaryl wherein Y⁵ isNR^(k), S or O; Y¹² is N; Y¹³ is C; and Y⁶, Y⁷, Y⁹, Y¹⁰, and Y¹¹ areindependently, C, CH, or CR¹⁵. For example, in certain embodiments, Z isa 5,6-bicyclic heteroaryl group of the formulae:

wherein z is 0, 1, 2, 3, 4 or 5 and R¹⁵ and R¹⁸ are defined below andherein. In certain embodiments, Z is an unsubstituted 5,6-bicyclicheteroaryl (i.e., wherein z is 0). In certain embodiments, Z is asubstituted 5,6-bicyclic heteroaryl (e.g., wherein z is 1, 2, 3, 4 or5). In certain embodiments, Z is a monosubstituted 5,6-bicyclicheteroaryl (i.e., wherein z is 1). In certain embodiments, Z is adisubstituted 5,6-bicyclic heteroaryl (i.e., wherein z is 2). In certainembodiments, Z is a trisubstituted 5,6-bicyclic heteroaryl (i.e.,wherein z is 3). In certain embodiments, z is 0, 1, 2 or 3. In certainembodiments, z is 0, 1 or 2. In certain embodiments, z is 0 or 1.

In certain embodiments, Z is a 5,6-bicyclic heteroaryl wherein Y⁷ is O,S, or NR^(k); Y¹² is N; Y¹³ is C; and Y⁵, Y⁶; Y⁹; Y¹⁰ and Y¹¹ areindependently, C, CH, or CR¹⁵. For example, in certain embodiments, Z isa 5,6-bicyclic heteroaryl group of the formulae:

wherein z is 0, 1, 2, 3, 4 or 5 and R¹⁵ and R¹⁸ are defined below andherein. In certain embodiments, Z is an unsubstituted 5,6-bicyclicheteroaryl (i.e., wherein z is 0). In certain embodiments, Z is asubstituted 5,6-bicyclic heteroaryl (e.g., wherein z is 1, 2, 3, 4 or5). In certain embodiments, Z is a monosubstituted 5,6-bicyclicheteroaryl (i.e., wherein z is 1). In certain embodiments, Z is adisubstituted 5,6-bicyclic heteroaryl (i.e., wherein z is 2). In certainembodiments, Z is a trisubstituted 5,6-bicyclic heteroaryl (i.e.,wherein z is 3). In certain embodiments, z is 0, 1, 2 or 3. In certainembodiments, z is 0, 1 or 2. In certain embodiments, z is 0 or 1.

In certain embodiments, Z is a 5,6-bicyclic heteroaryl wherein Y⁵ isselected from O, S, or NR¹⁸; Y¹³ is N; and Y⁶, Y⁷, Y⁸, Y⁹ and Y¹⁰ areindependently, C, CH, or CR¹⁵. For example, in certain embodiments, Z isa 5,6-bicyclic heteroaryl group of the formulae:

wherein z is 0, 1, 2, 3, 4 or 5 and R¹⁵ and R¹⁸ are defined below andherein. In certain embodiments, Z is an unsubstituted 5,6-bicyclicheteroaryl (i.e., wherein z is 0). In certain embodiments, Z is asubstituted 5,6-bicyclic heteroaryl (e.g., wherein z is 1, 2, 3, 4 or5). In certain embodiments, Z is a monosubstituted 5,6-bicyclicheteroaryl (i.e., wherein z is 1). In certain embodiments, Z is adisubstituted 5,6-bicyclic heteroaryl (i.e., wherein z is 2). In certainembodiments, Z is a trisubstituted 5,6-bicyclic heteroaryl (i.e.,wherein z is 3). In certain embodiments, z is 0, 1, 2 or 3. In certainembodiments, z is 0, 1 or 2. In certain embodiments, z is 0 or 1.

In certain embodiments, Z is a 10-membered heteroaryl (e.g., a6,6-bicyclic heteroaryl). In certain embodiments, Z is a 6,6-bicyclicheteroaryl substituted with 0, 1, 2, 3, 4 or 5 R¹⁵ groups. In certainembodiments, Z is a 6,6-bicyclic heteroaryl selected fromnaphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl,quinoxalinyl, phthalazinyl and quinazolinyl, wherein such groups aresubstituted with 0, 1, 2, 3, 4 or 5 R¹⁵ groups.

For example, in certain embodiments, Z is a 6,6-bicyclic heteroaryl ofthe formula:

wherein W⁶, W⁷, W⁸, W⁹, W¹⁰, W¹¹, W¹², and W¹³ are independently,selected from C, CH, CR¹⁵ or N, with the proviso that at least one ofW⁶, W⁷, W⁸, W⁹, W¹⁰, W¹¹, W¹², and W¹³ is N, and wherein R¹⁵ is asdefined below and herein.

In certain embodiments, Z is a quinolinyl group; e.g., of the formula(ii-g) wherein W⁹ is N and W⁶, W⁷, W⁸, W¹⁰, W¹¹, W¹² and W¹³ areindependently, C, CH, or CR¹⁵. For example, in certain embodiments, Z isa quinolinyl group of the formulae:

wherein z is 0, 1, 2, 3, 4 or 5, and R¹⁵ is as defined below and herein.In certain embodiments, Z is an unsubstituted quinolinyl (i.e., whereinz is 0). In certain embodiments, Z is a substituted quinolinyl (e.g.,wherein z is 1, 2, 3, 4 or 5). In certain embodiments, Z is amonosubstituted quinolinyl (i.e., wherein z is 1). In certainembodiments, Z is a disubstituted quinolinyl (i.e., wherein z is 2). Incertain embodiments, Z is a trisubstituted quinolinyl (i.e., wherein zis 3). In certain embodiments, z is 0, 1, 2 or 3. In certainembodiments, z is 0, 1 or 2. In certain embodiments, z is 0 or 1.

In certain embodiments, Z is an isoquinolinyl group; e.g., of theformula (ii-g) wherein W⁸ is N and W⁶, W⁷, W⁹, W¹⁰, W¹¹, W¹² and W¹³ areindependently, C, CH, or CR¹⁵. For example, in certain embodiments, Z isan isoquinolinyl group of the formulae:

wherein z is 0, 1, 2, 3, 4 or 5, and R¹⁵ is as defined below and herein.In certain embodiments, Z is an unsubstituted isoquinolinyl (i.e.,wherein z is 0). In certain embodiments, Z is a substitutedisoquinolinyl (e.g., wherein z is 1, 2, 3, 4 or 5). In certainembodiments, Z is a monosubstituted isoquinolinyl (i.e., wherein z is1). In certain embodiments, Z is a disubstituted isoquinolinyl (i.e.,wherein z is 2). In certain embodiments, Z is a trisubstitutedisoquinolinyl (i.e., wherein z is 3). In certain embodiments, z is 0, 1,2 or 3. In certain embodiments, z is 0, 1 or 2. In certain embodiments,z is 0 or 1.

In certain embodiments, Z is a quinoxalinyl group; e.g., of the formula(ii-g) wherein W⁶ and W⁹ are N and W⁷, W⁸, W¹⁰, W¹¹, W¹² and W¹³ are,independently, C, CH, or CR¹⁵. For example, in certain embodiments, Z isa quinoxalinyl group of the formulae:

wherein z is 0, 1, 2, 3, 4 or 5, and R¹⁵ is as defined below and herein.In certain embodiments, Z is an unsubstituted quinoxalinyl (i.e.,wherein z is 0). In certain embodiments, Z is a substituted quinoxalinyl(e.g., wherein z is 1, 2, 3, 4 or 5). In certain embodiments, Z is amonosubstituted quinoxalinyl (i.e., wherein z is 1). In certainembodiments, Z is a disubstituted quinoxalinyl (i.e., wherein z is 2).In certain embodiments, Z is a trisubstituted quinoxalinyl (i.e.,wherein z is 3). In certain embodiments, z is 0, 1, 2 or 3. In certainembodiments, z is 0, 1 or 2. In certain embodiments, z is 0 or 1.

In certain embodiments, Z is a 3-14 membered heterocyclyl. In certainembodiments, Z is a 3-14 membered heterocyclyl substituted with 0, 1, 2,3, 4 or 5 R¹⁵ groups. In certain embodiments, Z is a 5-10 memberedheterocyclyl substituted with 0, 1, 2, 3, 4 or 5 R¹⁵ groups. In certainembodiments, Z is a 5-8 membered heterocyclyl substituted with 0, 1, 2,3, 4 or 5 R¹⁵ groups. In certain embodiments, Z is a 5-6 memberedheterocyclyl substituted with 0, 1, 2, 3, 4 or 5 R¹⁵ groups. In certainembodiments, Z is a 9-10 membered heterocyclyl substituted with 0, 1, 2,3, 4 or 5 R¹⁵ groups.

Exemplary heterocyclyl Z groups include, but are not limited to,azirdinyl, oxiranyl, thiorenyl, azetidinyl, oxetanyl, thietanyl,tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl,dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, pyrrolyl-2,5-dione,dioxolanyl, oxathiolanyl, dithiolanyl, triazolinyl, oxadiazolinyl,thiadiazolinyl, piperidinyl, tetrahydropyranyl, dihydropyridinyl,thianyl, piperazinyl, morpholinyl, dithianyl, dioxanyl, triazinanyl,azepanyl, oxepanyl, thiepanyl, azocanyl, oxecanyl, thiocanyl, indolinyl,isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl,tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl,tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl,decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl,decahydronaphthyridinyl, decahydro-1,8-naphthyridinyl,octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl,chromanyl, chromenyl, 1H-benzo[e][1,4]diazepinyl,1,4,5,7-tetrahydro-pyrano[3,4-b]pyrrolyl,5,6-dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl,5,7-dihydro-4H-thieno[2,3-c]pyranyl,2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3-b]pyridinyl,4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridinyl,4,5,6,7-tetra-hydrofuro[3,2-c]pyridinyl, and4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl,1,2,3,4-tetrahydro-1,6-naphthyridinyl, wherein such groups aresubstituted with 0, 1, 2, 3, 4 or 5 R¹⁵ groups.

In certain embodiments, Z is a 6-membered heterocyclyl. In certainembodiments, Z is a 6-membered heterocyclyl substituted with 0, 1, 2, 3,4 or 5 R¹⁵ groups. In certain embodiments, Z is a 6-memberedheterocyclyl selected from piperidinyl, tetrahydropyranyl,dihydropyridinyl, thianyl, piperazinyl, morpholinyl, dithianyl,dioxanyl, and triazinanyl, wherein such groups are substituted with 0,1, 2, 3, 4 or 5 R¹⁵ groups.

For example, in certain embodiments, Z is a 6-membered heterocyclyl ofthe formula:

wherein W¹⁴, W¹⁵, W¹⁶, W¹⁷, W¹⁸ are, independently, CH₂, CHR¹⁵, C(R¹⁵)₂,NR¹⁸, O or S, and W¹⁹ is N, CH or CR¹⁵, with the proviso that at leastone of W¹⁴, W¹⁵, W¹⁶, W¹⁷, W¹⁸, and W¹⁹ is N, NR¹⁸, O or S, and whereinR¹⁵ and R¹⁸ are defined below and herein.

In certain embodiments, Z is a piperidinyl group. In certainembodiments, Z is a piperidinyl group substituted with 0, 1, 2, 3, 4 or5 R¹⁵ groups, e.g., of the formulae:

wherein z is 0, 1, 2, 3, 4 or 5, and R¹⁵ and R¹⁸ are as defined belowand herein. In certain embodiments, Z is an unsubstituted piperidinyl(i.e., wherein z is 0). In certain embodiments, Z is a substitutedpiperidinyl (e.g., wherein z is 1, 2, 3, 4 or 5). In certainembodiments, Z is a monosubstituted piperidinyl (i.e., wherein z is 1).In certain embodiments, Z is a disubstituted piperidinyl (i.e., whereinz is 2). In certain embodiments, Z is a trisubstituted piperidinyl(i.e., wherein z is 3). In certain embodiments, z is 0, 1, 2 or 3. Incertain embodiments, z is 0, 1 or 2. In certain embodiments, z is 0 or1.

In certain embodiments, Z is a 1-piperidinyl group, e.g., of the formula(ii-h) wherein W¹⁹ is N and W¹⁴, W¹⁵, W¹⁶, W¹⁷, and W¹⁸ are,independently, selected from CH₂, CHR¹⁵, C(R¹⁵)₂. In certainembodiments, Z is a 2-piperidinyl group, e.g., of the formula (ii-h)wherein W¹⁴ is NR¹⁸; W¹⁵, W¹⁶, W¹⁷, and W¹⁸ are, independently, CHR¹⁵,C(R¹⁵)₂, or CH₂; and W¹⁹ is CH or CR¹⁵. In certain embodiments, Z is a3-piperidinyl group, e.g., of the formula (ii-h) wherein W¹⁵ is NR¹⁸;W¹⁴, W¹⁶, W¹⁷ and W¹⁸ are, independently, CHR¹⁵, C(R¹⁵)₂, or CH₂; andW¹⁹ is CH or CR¹⁵. In certain embodiments, Z is a 4-piperidinyl group,e.g., of the formula (ii-h) wherein W¹⁶ is NR¹⁸; W¹⁴, W¹⁵, W¹⁷, and W¹⁸are, independently, CHR¹⁵, C(R¹⁵)₂, or CH₂; and W¹⁹ is CH or CR¹⁵.

In certain embodiments, Z is a piperazinyl group. In certainembodiments, Z is a piperazinyl group substituted with 0, 1, 2, 3 or 4R¹⁵ groups, e.g., of the formulae:

wherein x is 0, 1, 2, 3, 4 or 5, and R¹⁵ and R¹⁸ are as defined belowand herein. In certain embodiments, Z is an unsubstituted piperazinyl(i.e., wherein z is 0). In certain embodiments, Z is a substitutedpiperazinyl (e.g., wherein z is 1, 2, 3, 4 or 5). In certainembodiments, Z is a monosubstituted piperazinyl (i.e., wherein z is 1).In certain embodiments, Z is a disubstituted piperazinyl (i.e., whereinz is 2). In certain embodiments, Z is a trisubstituted piperazinyl(i.e., wherein z is 3). In certain embodiments, z is 0, 1, 2 or 3. Incertain embodiments, z is 0, 1 or 2. In certain embodiments, z is 0 or1.

In certain embodiments, Z is a piperazinyl group, e.g., of the formula(ii-h) wherein W¹⁹ is N, W¹⁶ is NR¹⁸, and W¹⁴, W¹⁵, W¹⁶, W¹⁷, and W¹⁸are independently, CHR¹⁵, C(R¹⁵)₂, or CH₂. In certain embodiments, Z isa piperazinyl group wherein W¹⁹ is CH or CR¹⁵, W¹⁴ and W¹⁷ areindependently NR¹⁸, and W¹⁵, W¹⁶, and W¹⁸ are, independently, CHR¹⁵,C(R¹⁵)₂, or CH₂.

In certain embodiments, Z is a morpholinyl group substituted with 0, 1,2, 3 or 4 R¹⁵ groups, e.g., of the formulae:

wherein z is 0, 1, 2, 3, 4 or 5, and R¹⁵ and R¹⁸ are as defined belowand herein. In certain embodiments, Z is an unsubstituted morpholinyl(i.e., wherein z is 0). In certain embodiments, Z is a substitutedmorpholinyl (e.g., wherein z is 1, 2, 3, 4 or 5). In certainembodiments, Z is a monosubstituted morpholinyl (i.e., wherein z is 1).In certain embodiments, Z is a disubstituted morpholinyl (i.e., whereinz is 2). In certain embodiments, Z is a trisubstituted morpholinyl(i.e., wherein z is 3). In certain embodiments, z is 0, 1, 2 or 3. Incertain embodiments, z is 0, 1 or 2. In certain embodiments, z is 0 or1.

In certain embodiments, Z is a morpholinyl group; e.g., of the formula(ii-h) wherein W¹⁹ is N, W¹⁶ is 0 and W¹⁴, W¹⁵, W¹⁶, and W¹⁷ are,independently, selected from CH₂, CHR¹⁵, C(R¹⁵)₂. In certainembodiments, Z is a morpholinyl group wherein W¹⁹ is CH or CR¹⁵, W¹⁴ andW¹⁷ are independently selected from O and NR¹⁸, and W¹⁵, W¹⁶, and W¹⁸are, independently, CHR¹⁵, C(R¹⁵)₂, or CH₂.

In certain embodiments, Z is a dioxanyl group. In certain embodiments, Zis a dioxanyl group substituted with 0, 1, 2, 3 or 4 R¹⁵ groups, e.g.,of the formulae:

wherein z is 0, 1, 2, 3, 4 or 5, and R¹⁵ is as defined below and herein.In certain embodiments, Z is an unsubstituted dioxanyl (i.e., wherein zis 0). In certain embodiments, Z is a substituted dioxanyl (e.g.,wherein z is 1, 2, 3, 4 or 5). In certain embodiments, Z is amonosubstituted dioxanyl (i.e., wherein z is 1). In certain embodiments,Z is a disubstituted dioxanyl (i.e., wherein z is 2). In certainembodiments, Z is a trisubstituted dioxanyl (i.e., wherein z is 3). Incertain embodiments, z is 0, 1, 2 or 3. In certain embodiments, z is 0,1 or 2. In certain embodiments, z is 0 or 1.

In certain embodiments, Z is a dioxanyl group, e.g., of the formula(ii-h) wherein W¹⁴ and W¹⁷ are 0 and W¹⁵, W¹⁶, and W¹⁸ are,independently, CHR¹⁵, C(R¹⁵)₂, or CH₂; and W¹⁹ is CH or CR¹⁵. In certainembodiments, Z is a dioxanyl group wherein W¹⁹ is CH or CR¹⁵, W¹⁴ andW¹⁶ are independently selected from 0, and W¹⁵, W¹⁷, and W¹⁸ are,independently, CHR¹⁵, C(R¹⁵)₂, or CH₂. In certain embodiments, Z is adioxanyl group wherein W¹⁹ is CH or CR¹⁵, W¹⁵ and W¹⁷ are independentlyselected from 0, and W¹⁴, W¹⁶, and W¹⁸ are, independently, CHR¹⁵,C(R¹⁵)₂, or CH₂.

In certain embodiments, Z is a C₃₋₁₀ carbocycyl. In certain embodiments,Z is a C₃₋₁₀ carbocycyl substituted with 0, 1, 2, 3, 4 or 5 R¹⁵ groups.In certain embodiments, Z is a C₅₋₈ carbocycyl substituted with 0, 1, 2,3, 4 or 5 R¹⁵ groups. In certain embodiments, Z is a C₅₋₆ carbocycylsubstituted with 0, 1, 2, 3, 4 or 5 R¹⁵ groups. In certain embodiments,Z is a C₉₋₁₀ carbocycyl substituted with 0, 1, 2, 3, 4 or 5 R¹⁵ groups.

R¹⁵ Groups

As used herein, each instance of R¹⁵ is, independently, selected fromhalogen (i.e., fluoro (—F), bromo (—Br), chloro (—Cl), and iodo (—CN,—NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR¹⁶, —ON(R¹⁸)₂, —N(R¹⁸)₂, —N(R¹⁸)₃ ⁺X⁻,—N(OR¹⁷)R¹⁸, —SH, —SR¹⁶, —SSR¹⁷, —C(═O)R¹⁶, —CO₂H, —CHO, —CO₂R¹⁶,—OC(═O)R¹⁶, —OCO₂R¹⁶, —C(═O)N(R¹⁸)₂, —OC(═O)N(R¹⁸)₂, —NR¹⁸C(═O)R¹⁶,—NR¹⁸CO₂R¹⁶, —NR¹⁸C(═O)N(R¹⁸)₂, —C(═NR¹⁸)R¹⁶, —C(═NR¹⁸)OR¹⁶,—OC(═NR¹⁸)R¹⁶, —OC(═NR¹⁸)OR¹⁶, —C(═NR¹⁸)N(R¹⁸)₂, —OC(═NR¹⁸)N(R¹⁸)₂,—NR¹⁸C(═NR¹⁸)N(R¹⁸)₂, —C(═O)NR¹⁸SO₂R¹⁶, —NR¹⁸SO₂R¹⁶, —SO₂N(R¹⁸)₂,—SO₂R¹⁶, —SO₂OR¹⁶, —OSO₂R¹⁶, —S(═O)R¹⁶, —OS(═O)R¹⁶, —Si(R¹⁶)₃,—OSi(R¹⁶)₃ —C(═S)N(R¹⁸)₂, —C(═O)SR¹⁶, —C(═S)SR¹⁶, —SC(S)SR¹⁶,—P(═O)₂R¹⁶, —OP(═O)₂R¹⁶, —P(═O)(R¹⁶)₂, —OP(—O)(R¹⁶)₂, —OP(═O)(OR¹⁷)₂,—P(═O)₂N(R¹⁸)₂, —OP(═O)₂N(R¹⁸)₂, —P(═O)(NR¹⁸)₂, —OP(═O)(NR¹⁸)₂,—NR¹⁸P(═O)(OR¹⁷)₂, —NR¹⁸P(═O)(NR¹⁸)₂, —P(R¹⁷)₂, —P(R¹⁷)₃, —OP(R¹⁷)₂,—OP(R¹⁷)₃, —B(OR¹⁷)₂, —BR¹⁶(OR¹⁷), C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl,C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₄ carbocyclyl, 3-14 memberedheterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroaryl, wherein eachalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroarylis independently substituted with 0, 1, 2, 3, 4, or 5 R¹⁹ groups; or twovicinal R¹⁵ groups are replaced with the group —O(C(R²)₂)₁₋₂O— whereineach R² is independently H, C₁₋₆ alkyl or halogen;

each instance of R¹⁶ is, independently, selected from C₁₋₁₀ alkyl, C₁₋₁₀perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocyclyl, 3-14membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroaryl, whereineach alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R¹⁹groups;

each instance of R¹⁸ is, independently, selected from hydrogen, —OH,—OR¹⁶, —N(R¹⁷)₂, —C(═O)R¹⁶, —C(═O)N(R¹⁷)₂, —CO₂R¹⁶, —SO₂R¹⁶,—C(═NR¹⁷)OR¹⁶, —C(═NR¹⁷)N(R¹⁷)₂, —SO₂N(R¹⁷)₂, —SO₂R¹⁷, —SO₂OR¹⁷, —SOR¹⁶,—C(═S)N(R¹⁷)₂, —C(═O)SR¹⁷, —C(═S)SR¹⁷, —P(═O)₂R¹⁶, —P(═O)(R¹⁶)₂,—P(═O)₂N(R¹⁷)₂, —P(═O)(NR¹⁷)₂, C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocyclyl, 3-14 membered heterocyclyl,C₆₋₁₄ aryl, and 5-14 membered heteroaryl, or two R¹⁷ groups attached toan N atom are joined to form a 3-14 membered heterocyclyl or 5-14membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3, 4, or 5 R¹⁹ groups;

each instance of R¹⁷ is, independently, selected from hydrogen, C₁₋₁₀alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 memberedheteroaryl, or two R¹⁷ groups attached to an N atom are joined to form a3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, whereineach alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R¹⁹groups;

each instance of R¹⁹ is, independently, selected from halogen, —CN,—NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR²⁰, —ON(R²¹)₂, —N(R²¹)₂, —N(R²¹)₃ ⁺X⁻,—N(OR²⁰)R²¹, —SH, —SR^(N), —SSR²⁰, —C(═O)R²⁰, —CO₂H, —CO₂R²⁰,—OC(═O)R²⁰, —OCO₂R²⁰, —C(═O)N(R²¹)₂, —OC(═O)N(R²¹)₂, —NR²¹C(═O)R²⁰,—NR²¹CO₂R²⁰, —NR²¹C(═O)N(R²¹)₂, —C(═NR²¹)OR²⁰, —OC(═NR²¹)R²⁰,—OC(═NR²¹)OR²⁰, —C(═NR²¹)N(R²¹)₂, —OC(═NR²¹)N(R²¹)₂,—NR²¹C(═NR²¹)N(R²¹)₂, —NR²¹SO₂R²⁰, —SO₂N(R²¹)₂, —SO₂R²⁰, —SO₂OR²⁰,—OSO₂R²⁰, —S(═O)R²⁰, —Si(R²⁰)₃, —Si(R²⁰)₃, —C(═S)N(R²¹)₂, —C(═O)SR²⁰,—C(═S)SR²⁰, —SC(═S)SR²⁰, —P(═O)₂R²⁰, —P(═O)(R²⁰)₂, —OP(═O)(R²⁰)₂,—OP(═O)(OR²⁰)₂, C₁₋₆ alkyl, C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ carbocyclyl, 3-10 membered heterocyclyl, C₆₋₁₀ aryl, 5-10membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl,heterocyclyl, aryl, and heteroaryl is independently substituted with 0,1, 2, 3, 4, or 5 R²² groups, or two geminal R¹⁹ substituents can bejoined to form ═O or ═S;

each instance of R²⁰ is, independently, selected from C₁₋₆ alkyl, C₁₋₆perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl, C₆₋₁₀ aryl,3-10 membered heterocyclyl, and 3-10 membered heteroaryl, wherein eachalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroarylis independently substituted with 0, 1, 2, 3, 4, or 5 R²² groups;

each instance of R²¹ is, independently, selected from hydrogen, C₁₋₆alkyl, C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl,3-10 membered heterocyclyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl, ortwo R²¹ groups attached to an N atom are joined to form a 3-14 memberedheterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl,alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl isindependently substituted with 0, 1, 2, 3, 4, or 5 R²² groups; and

each instance of R²² is, independently, halogen, —CN, —NO₂, —N₃, —SO₂H,—SO₃H, —OH, —OC₁₋₆ alkyl, —ON(C₁₋₆ alkyl)₂, —N(C₁₋₆ alkyl)₂, —N(C₁₋₆alkyl)₃X, —NH(C₁₋₆ alkyl)₂X, —NH₂(C₁₋₆ alkyl)X, —NH₃X, —N(OC₁₋₆alkyl)(C₁₋₆ alkyl), —N(OH)(C₁₋₆ alkyl), —NH(OH), —SH, —SC₁₋₆ alkyl,—SS(C₁₋₆ alkyl), —C(═O)(C₁₋₆ alkyl), —CO₂H, —CO₂(C₁₋₆ alkyl),—OC(═O)(C₁₋₆ alkyl), —OCO₂(C₁₋₆ alkyl), —C(═O)NH₂, —C(═O)N(C₁₋₆ alkyl)₂,—OC(═O)NH(C₁₋₆ alkyl), —NHC(═O)(C₁₋₆ alkyl), —N(C₁₋₆ alkyl)C(═O)(C₁₋₆alkyl), —NHCO₂(C₁₋₆ alkyl), —NHC(═O)N(C₁₋₆ alkyl)₂, —NHC(═O)NH(C₁₋₆alkyl), —NHC(═O)NH₂, —C(═NH)O(C₁₋₆ alkyl), —OC(═NH)(C₁₋₆ alkyl),—OC(═NH)OC₁₋₆ alkyl, —C(═NH)N(C₁₋₆ alkyl)₂, —C(═NH)NH(C₁₋₆ alkyl),—C(═NH)NH₂, —OC(═NH)N(C₁₋₆ alkyl)₂, —OC(NH)NH(C₁₋₆ alkyl), —OC(NH)NH₂,—NHC(NH)N(C₁₋₆ alkyl)₂, —NHC(═NH)NH₂, —NHSO₂(C₁₋₆ alkyl), —SO₂N(C₁₋₆alkyl)₂, —SO₂NH(C₁₋₆ alkyl), —SO₂NH₂, —SO₂C₁₋₆ alkyl, —SO₂OC₁₋₆ alkyl,—OSO₂C₁₋₆ alkyl, —SOC₁₋₆ alkyl, —Si(C₁₋₆ alkyl)₃, —OSi(C₁₋₆ alkyl)₃—C(═S)N(C₁₋₆ alkyl)₂, C(═S)NH(C₁₋₆ alkyl), C(═S)NH₂, —C(═O)S(C₁₋₆alkyl), —C(═S)SC₁₋₆ alkyl, —SC(═S)SC₁₋₆ alkyl, —P(═O)₂(C₁₋₆ alkyl),—P(═O)(C₁₋₆ alkyl)₂, —OP(═O)(C₁₋₆ alkyl)₂, —OP(═O)(OC₁₋₆ alkyl)₂, C₁₋₆alkyl, C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂ alkynyl, C₃₋₁₀ carbocyclyl,C₆₋₁₀ aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; or twogeminal R²² substituents can be joined to form ═O or ═S;

wherein X⁻ is a counterion.

In certain embodiments, each instance of R¹⁵ is, independently, selectedfrom fluoro (—F), bromo (—Br), chloro (—Cl), and iodo (—I), —OR¹⁶,—C(O)N(R¹⁸)², —SO₂N(R¹⁸)₂, C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀alkenyl, C₂₋₁₀ alkynyl, C₆₋₁₄ aryl, and 5-14 membered heteroaryl,wherein each alkyl, alkenyl, alkynyl, aryl, and heteroaryl isindependently substituted with 0, 1, 2, 3, 4, or 5 R¹⁹ groups.

In certain embodiments, R¹⁵ is, independently, selected from fluoro(—F), bromo (—Br), chloro (—Cl), and iodo (—I), —OR¹⁶ and C₁₋₁₀perhaloalkyl. In certain embodiments, R¹⁵ is, independently, selectedfrom fluoro (—F), bromo (—Br), chloro (—Cl), and iodo (—I) and —OR¹⁶. Incertain embodiments, R¹⁵ is, independently, selected from fluoro (—F),bromo (—Br), chloro (—Cl), and iodo (—I) and C₁₋₁₀ perhaloalkyl.

In certain embodiments, R¹⁵ is selected from —OR¹⁶ and C₁₋₁₀perhaloalkyl.

In certain embodiments, R¹⁵ is —OR¹⁶. In certain embodiments, R¹⁶ isselected from C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, C₆₋₁₀ aryl, and 5-6 membered heteroaryl, wherein each alkyl,alkenyl, alkynyl, aryl, and heteroaryl is independently substituted with0, 1, 2, 3, 4, or 5 R¹⁹ groups.

In certain embodiments, R¹⁵ is —OR¹⁶, and R¹⁶ is selected from C₁₋₁₀alkyl. In certain embodiments, R¹⁵ is —OR¹⁶, and R¹⁶ is selected fromC₁₋₆ alkyl. In certain embodiments, R¹⁵ is —OR¹⁶, and R¹⁶ is selectedfrom C₁₋₄ alkyl. In certain embodiments, R¹⁵ is —OR¹⁶, and R¹⁶ isselected from C₁₋₂ alkyl. In certain embodiments, R¹⁵ is —OR¹⁶ and R¹⁶is —CH₃, -Et, -iPr, -nBu, -n-pentyl. In certain embodiments, R¹⁵ is—OR¹⁶ and R¹⁶ is —CH₃.

In certain embodiments, R¹⁵ is —OR¹⁶, and R¹⁶ is selected from C₁₋₁₀perhaloalkyl. In certain embodiments, R¹⁵ is —OR¹⁶, and R¹⁶ is selectedfrom C₁₋₆ perhaloalkyl. In certain embodiments, R¹⁵ is —OR¹⁶, and R¹⁶ isselected from C₁₋₄ perhaloalkyl. In certain embodiments, R¹⁵ is —OR¹⁶,and R¹⁶ is selected from C₁₋₄ perhaloalkyl. In certain embodiments, R¹⁵is —OR¹⁶ and R¹⁶ is —CF₃, —CF₂CF₃, —CF₂CF₂CF₃, —CCl₃, —CFCl₂, or —CF₂Cl.In certain embodiments, R¹⁵ is —OR¹⁶ and R¹⁶ is —CF₃.

In certain embodiments, R¹⁵ is —OR¹⁶, and R¹⁶ is selected from C₂₋₁₀alkenyl. In certain embodiments, R¹⁵ is —OR¹⁶, and R¹⁶ is selected fromC₂ alkenyl. In certain embodiments, R¹⁵ is —OR¹⁶, and R¹⁶ is selectedfrom C₂ alkenyl. In certain embodiments, R¹⁵ is —OR¹⁶, and R¹⁶ isselected from —CH₂CHCH₂ (i.e., allyl).

In certain embodiments, R¹⁵ is —OR¹⁶, and R¹⁶ is selected from C₂₋₁₀alkynyl. In certain embodiments, R¹⁵ is —OR¹⁶, and R¹⁶ is selected fromC₂₋₆ alkynyl. In certain embodiments, R¹⁵ is —OR¹⁶, and R¹⁶ is selectedfrom C₂₋₄ alkynyl. In certain embodiments, R¹⁵ is —OR¹⁶, and R¹⁶ isselected from —CH₂CCH (i.e., propargyl).

In certain embodiments, R¹⁵ is —OR¹⁶, and R¹⁶ is selected from C₆ aryl(e.g., phenyl) substituted with 0, 1, 2, 3 or 4 R¹⁹ groups. In certainembodiments, R¹⁵ is —OR¹⁶, and R¹⁶ is phenyl substituted with 0, 1 or 2R¹⁹ groups. In certain embodiments, R¹⁵ is —OR¹⁶, and R¹⁶ is phenylsubstituted with 1 R¹⁹ groups. In certain embodiments, R¹⁵ is —OR¹⁶, andR¹⁶ is phenyl substituted with 0 R¹⁹ groups (i.e., —C₆H₅).

In certain embodiments, R¹⁵ is —OR¹⁶, and R¹⁶ is selected from 5-6membered heteroaryl substituted with 0, 1, 2, 3 or 4 R¹⁹ groups. Incertain embodiments, R¹⁵ is —OR¹⁶, and R¹⁶ is selected from a 6 memberedheteroaryl substituted with 0, 1, 2, 3 or 4 R¹⁹ groups. In certainembodiments, R¹⁵ is —OR¹⁶, and R¹⁶ is selected from pyridinyl (e.g.,2-pyridinyl, 3-pyridinyl, 4-pyridinyl) substituted with 0, 1, 2, 3 or 4R¹⁹ groups. In certain embodiments, R¹⁵ is —OR¹⁶, and R¹⁶ is selectedfrom pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl)substituted with 0, 1, 2 or 3 R¹⁹ groups.

In certain embodiments, R¹⁵ is —C(═O)N(R¹⁸)₂.

In certain embodiments, R¹⁵ is —SO₂N(R-18)₂.

In certain embodiments, R¹⁵ is C₁₋₁₀ perhaloalkyl. In certainembodiments, R¹⁵ is C₁₋₆ perhaloalkyl. In certain embodiments, R¹⁵ isC₁₋₄ perhaloalkyl. In certain embodiments, R¹⁵ is C₁₋₂ perhaloalkyl. Incertain embodiments, R¹⁵ is selected from —CF₃, —CF₂CF₃, —CF₂CF₂CF₃,—CCl₃, —CFCl₂, and —CF₂C1. In certain embodiments, R¹⁵ is selected from—CF₃.

In certain embodiments, R¹⁵ is C₁₋₁₀ alkyl substituted with 0, 1, 2, 3,4, or 5 R¹⁹ groups. In certain embodiments, R¹⁵ is C₁₋₆ alkylsubstituted with 0, 1, 2, 3, 4, or 5 R¹⁹ groups. R¹⁵ is C_(i) alkylsubstituted with 0, 1, 2, 3, 4, or 5 R¹⁹ groups. In certain embodiments,the R¹⁵ alkyl group is unsubstituted (0 R¹⁹ groups). In certainembodiments, R¹⁵ is —CH₃, -Et, -iPr, -nBu, -n-pentyl.

In certain embodiments, R¹⁵ is C₂₋₁₀ alkenyl substituted with 0, 1, 2,3, 4, or 5 R¹⁹ groups. In certain embodiments, R¹⁵ is C₂₋₆ alkenylsubstituted with 0, 1, 2, 3 or 4 R¹⁹ groups. In certain embodiments, R¹⁵is C₂₋₄ alkenyl substituted with 0, 1, 2 or 3 R¹⁹ groups. In certainembodiments, the R¹⁵ alkenyl group is unsubstituted (0 R¹⁹ groups). Incertain embodiments, R¹⁵ is —CH₂CHCH₂ (i.e., allyl),

In certain embodiments, R¹⁵ is C₂₋₁₀ alkynyl substituted with 0, 1, 2,3, 4, or 5 R¹⁹ groups. In certain embodiments, R¹⁵ is C₂ alkynylsubstituted with 0, 1, 2 or 3 R¹⁹ groups. In certain embodiments, R¹⁵ isC₂₋₄ alkynyl substituted with 0, 1 or 2 R¹⁹ groups. In certainembodiments, the R¹⁵ alkynyl group is unsubstituted (0 R¹⁹ groups). Incertain embodiments, R¹⁵ is —CH₂CCH (i.e., propargyl).

In certain embodiments, R¹⁵ is C₆₋₁₄ aryl. In certain embodiments, R¹⁵is selected from C₆ aryl (e.g., phenyl) substituted with 0, 1, 2, 3 or 4R¹⁹ groups. In certain embodiments, R¹⁵ is an unsubstituted phenyl. Incertain embodiments, R¹⁵ is a monosubstituted phenyl (i.e., substitutedwith 1 R¹⁹ group).

In certain embodiments, R¹⁵ is 5-14 membered heteroaryl substituted with0, 1, 2, 3, 4, or 5 R¹⁹ groups. In certain embodiments, R¹⁵ is 5-6membered heteroaryl substituted with 0, 1, 2, 3 or 4 R¹⁹ groups. Incertain embodiments, R¹⁵ is a 6-membered heteroaryl substituted with 0,1, 2, 3 or 4 R¹⁹ groups. In certain embodiments, R¹⁵ is pyridinyl (e.g.,2-pyridinyl, 3-pyridinyl, 4-pyridinyl) substituted with 0, 1, 2, 3 or 4R¹⁹ groups. In certain embodiments, R¹⁵ is pyrimidinyl (e.g.,2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl) substituted with 0, 1, 2 or3 R¹⁹ groups. In certain embodiments, the R¹⁵ heteroaryl group isunsubstituted (0 R¹⁹ groups).

R¹⁸ Groups

In certain embodiments, each instance of R¹⁸ is, independently, selectedfrom —H, —OH, —OR¹⁶, —N(R¹⁷)₂, —C(═O)R¹⁶, —C(═O)N(R¹⁷)₂, —CO₂R¹⁶,—SO₂R¹⁶, —C(═NR¹⁷)R¹⁶, —C(═NR¹⁷)OR¹⁶, —C(═NR¹⁷)N(R¹⁷)₂, —SO₂N(R¹⁷)₂,—SO₂R¹⁶, —SO₂OR¹⁶, —SOR¹⁶, —C(═S)N(R¹⁷)₂, —C(═O)SR¹⁶, —C(═S)SR¹⁶, C₁₋₁₀alkyl (e.g., aralkyl), C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocyclyl,3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroarylgroups, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl,aralkyl, aryl, and heteroaryl is independently substituted with 0, 1, 2,3, 4, or 5 R¹⁹ groups, wherein R¹⁶, R¹⁷, R¹⁹ are as defined above andherein.

In certain embodiments, each instance of R¹⁷ is, independently, selectedfrom —H, —C(═O)R¹⁶, —C(═O)OR¹⁶, —SO₂R¹⁶, or C₁₋₆ alkyl. In certainembodiments, each instance of R¹⁷ is, independently, selected from —H orC₁₋₆ alkyl. In certain embodiments, each instance of R¹⁷ is,independently, selected from —H and —CH₃. In certain embodiments, eachinstance of R¹⁷ is, independently, selected from —H. In certainembodiments, each instance of R¹⁷ is, independently, selected from —CH₃.

Additional Embodiments of Compounds of Formula (I)

As defined generally above, the present invention provides compounds ofthe formula (I):

or a pharmaceutically acceptable form thereof, wherein G, R^(a), R^(b),R^(c) and R^(d) are as defined herein.

In one aspect, wherein R^(a), R^(b), R^(c) are each H, and R^(d) is thegroup Z, the present invention provides compounds of the formula (III):

or a pharmaceutically acceptable form thereof, wherein G and Z are asdefined herein. In certain embodiments, L is a covalent bond. In certainembodiments, G is —OR^(e). In certain embodiments, G is —Br. However, incertain embodiments, G is not halogen (e.g., —Br, —Cl, —I).

In certain embodiments, wherein Z is a 5-membered heteroaryl ring, thepresent invention provides compounds of the formula (III-a):

or a pharmaceutically acceptable form thereof, wherein Y¹, Y², Y³, Y⁴,G, L, R^(a), R^(b) and R^(c) are as defined herein. In certainembodiments, L is a covalent bond. In certain embodiments, G is —OR^(e).In certain embodiments, G is —Br. However, in certain embodiments, G isnot halogen (e.g., —Br, —Cl, —I). In certain embodiments, Y¹ is S, Y² isCR¹⁵, Y³ is N, and Y⁴ is CH or CR¹⁵, wherein R¹⁵ is as defined above andherein. In certain embodiments, Y⁴ is CH. In certain embodiments, thesubstituent present on Y² is C₆ aryl (e.g., phenyl).

In certain embodiments, wherein Z is a 6-membered heteroaryl ring, thepresent invention provides compounds of the formula (III-b):

or a pharmaceutically acceptable form thereof, wherein W₁, W₂, W₃, W₄,G, L, R^(a), R^(b) and R^(c) are as defined herein. In certainembodiments, L is a covalent bond. In certain embodiments, G is —OR^(e).In certain embodiments, G is —Br. However, in certain embodiments, G isnot halogen (e.g., —Br, —Cl, —I). In certain embodiments, the 6-memberedheteroaryl ring is pyridinyl (e.g., 2-pyridinyl, 3-pyridinyl,4-pyridinyl) or pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl,5-pyrimidinyl).

In certain embodiments, wherein Z is a 9-membered heteroaryl ring, thepresent invention provides compounds of the formula (III-c):

or a pharmaceutically acceptable form thereof, wherein Y⁵, Y⁶, Y⁷, Y⁹,Y¹⁰, Y¹¹, Y¹², Y¹³, G, L, R^(a), R^(b) and R^(c) are as defined herein.In certain embodiments, L is a covalent bond. In certain embodiments, Gis —OR^(e). In certain embodiments, G is —Br. However, in certainembodiments, G is not halogen (e.g., —Br, —Cl, —I).

In certain embodiments, wherein Z is a 10-membered heteroaryl ring, thepresent invention provides compounds of the formula (III-d):

or a pharmaceutically acceptable form thereof, wherein W⁶, W⁷, W⁸, W⁹,W¹⁰, W¹¹, W¹², W₁₃, G, L, R^(a), R^(b), R^(c) are as defined herein. Incertain embodiments, L is a covalent bond. In certain embodiments, G is—OR^(e). In certain embodiments, G is —Br. However, in certainembodiments, G is not halogen (e.g., —Br, —Cl, —I).

In certain embodiments, wherein Z is a 6-membered heterocycyl, thepresent invention provides compounds of the formula (III-e):

or a pharmaceutically acceptable form thereof, wherein W¹⁴, W¹⁵, W¹⁶,W¹⁷, W¹⁸, W¹⁹, G, L, R^(a), R^(b) and R^(c) are as defined herein. Incertain embodiments, L is a covalent bond. In certain embodiments, G is—OR^(e). In certain embodiments, G is —Br. However, in certainembodiments, G is not halogen (e.g., —Br, —Cl, —I).

Exemplary Compounds of the Present Invention

Exemplified compounds of formulae (I), (III), and subgenera thereof, aredepicted in Tables 1a to 1e, provided below, and are also described inmore detail in Examples 1-31, provided herein. Compounds were assayed asinhibitors of human FAAH using the Method described in detail in Example32.

In certain embodiments, the compound is any one of the compoundsprovided in Table 1a, or a pharmaceutically acceptable form thereof:

TABLE 1a

Com- pound G R^(a) R^(c) R¹⁵ R¹⁹ II-6  —Br —H —H —H —H II-21

—H —H —H —H II-28

—H —H —H —H II-18 —Br —H —CH₃ —H —H II-22

—H —CH₃ —H —H II-23

—H —CH₃ —H —H II-29

—H —CH₃ —H —H II-19 —Br —CH₃ —H —H —H (cis) II-20 —Br —CH₃ —H —H —H(trans) II-17 —Br —H —H —H —Cl

In certain embodiments, the compound is any one of the compoundsprovided in Table 1b, or a pharmaceutically acceptable form thereof:

TABLE 1b

Compound G R^(a) R^(c) II-25 —Br —H —H II-26

—H —H II-27

—H —H

In certain embodiments, the compound is any one of the compoundsprovided in Table 1c, or a pharmaceutically acceptable form thereof:

TABLE 1c

Compound G R^(a) R^(c) II-8  —Br —H —H II-31

—H —H II-30

—H —H

In certain embodiments, the compound is any one of the compoundsprovided in Table 1d, or a pharmaceutically acceptable form thereof:

TABLE 1d

Compound G R¹⁸ R^(a) R^(c) II-15 —Br

—H —H II-16 —Br

—H —H

In certain embodiments, the compound is any one of the compoundsprovided in Table 1e, or a pharmaceutically acceptable form thereof:

TABLE 1e

II-1

II-2

II-3

II-4

II-5

II-7

II-9

II-10

II-11

II-12

II-13

II-14

II-24

II-17

In certain embodiments of formulae (I) and (III), or subgenera thereof,any one of the following compounds, wherein R¹⁸ is as defined herein, isspecifically excluded:

II. Pharmaceutical Compositions

In certain embodiments, the present invention provides a pharmaceuticalcomposition comprising a compound of the formula (I) or apharmaceutically acceptable form thereof, and a pharmaceuticallyacceptable excipient.

Pharmaceutically acceptable excipients include any and all solvents,diluents or other liquid vehicles, dispersion or suspension aids,surface active agents, isotonic agents, thickening or emulsifyingagents, preservatives, solid binders, lubricants and the like, as suitedto the particular dosage form desired. General considerations in theformulation and/or manufacture of pharmaceutical compositions agents canbe found, for example, in Remington's Pharmaceutical Sciences, SixteenthEdition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980), andRemington: The Science and Practice of Pharmacy, 21^(st) Edition(Lippincott Williams & Wilkins, 2005).

Pharmaceutical compositions described herein can be prepared by anymethod known in the art of pharmacology. In general, such preparatorymethods include the steps of bringing the active ingredient intoassociation with a carrier and/or one or more other accessoryingredients, and then, if necessary and/or desirable, shaping and/orpackaging the product into a desired single- or multi-dose unit.

Pharmaceutical compositions can be prepared, packaged, and/or sold inbulk, as a single unit dose, and/or as a plurality of single unit doses.As used herein, a “unit dose” is discrete amount of the pharmaceuticalcomposition comprising a predetermined amount of the active ingredient.The amount of the active ingredient is generally equal to the dosage ofthe active ingredient which would be administered to a subject and/or aconvenient fraction of such a dosage such as, for example, one-half orone-third of such a dosage.

Relative amounts of the active ingredient, the pharmaceuticallyacceptable carrier, and/or any additional ingredients in apharmaceutical composition of the invention will vary, depending uponthe identity, size, and/or condition of the subject treated and furtherdepending upon the route by which the composition is to be administered.By way of example, the composition may comprise between 0.1% and 100%(w/w) active ingredient.

Pharmaceutically acceptable excipients used in the manufacture ofprovided pharmaceutical compositions include inert diluents, dispersingand/or granulating agents, surface active agents and/or emulsifiers,disintegrating agents, binding agents, preservatives, buffering agents,lubricating agents, and/or oils. Excipients such as cocoa butter andsuppository waxes, coloring agents, coating agents, sweetening,flavoring, and perfuming agents may also be present in the composition.

Exemplary diluents include calcium carbonate, sodium carbonate, calciumphosphate, dicalcium phosphate, calcium sulfate, calcium hydrogenphosphate, sodium phosphate lactose, sucrose, cellulose,microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodiumchloride, dry starch, cornstarch, powdered sugar, etc., and combinationsthereof.

Exemplary granulating and/or dispersing agents include potato starch,corn starch, tapioca starch, sodium starch glycolate, clays, alginicacid, guar gum, citrus pulp, agar, bentonite, cellulose and woodproducts, natural sponge, cation-exchange resins, calcium carbonate,silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone)(crospovidone), sodium carboxymethyl starch (sodium starch glycolate),carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose(croscarmellose), methylcellulose, pregelatinized starch (starch 1500),microcrystalline starch, water insoluble starch, calcium carboxymethylcellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate,quaternary ammonium compounds, etc., and combinations thereof.

Exemplary surface active agents and/or emulsifiers include naturalemulsifiers (e.g. acacia, agar, alginic acid, sodium alginate,tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk,casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g.bentonite [aluminum silicate] and Veegum [magnesium aluminum silicate]),long chain amino acid derivatives, high molecular weight alcohols (e.g.stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate,ethylene glycol distearate, glyceryl monostearate, and propylene glycolmonostearate, polyvinyl alcohol), carbomers (e.g. carboxy polymethylene,polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer),carrageenan, cellulosic derivatives (e.g. carboxymethylcellulose sodium,powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose,hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acidesters (e.g. polyoxyethylene sorbitan monolaurate [Tween 20],polyoxyethylene sorbitan [Tween 60], polyoxyethylene sorbitan monooleate[Tween 80], sorbitan monopalmitate [Span 40], sorbitan monostearate[Span 60], sorbitan tristearate [Span 65], glyceryl monooleate, sorbitanmonooleate [Span 80]), polyoxyethylene esters (e.g. polyoxyethylenemonostearate [Myrj 45], polyoxyethylene hydrogenated castor oil,polyethoxylated castor oil, polyoxymethylene stearate, and Solutol),sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g.Cremophor), polyoxyethylene ethers, (e.g. polyoxyethylene lauryl ether[Brij 30]), poly(vinyl-pyrrolidone), diethylene glycol monolaurate,triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate,oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic F 68,Poloxamer 188, cetrimonium bromide, cetylpyridinium chloride,benzalkonium chloride, docusate sodium, etc. and/or combinationsthereof.

Exemplary binding agents include starch (e.g. cornstarch and starchpaste), gelatin, sugars (e.g. sucrose, glucose, dextrose, dextrin,molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums(e.g. acacia, sodium alginate, extract of Irish moss, panwar gum, ghattigum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose,ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose,hydroxypropyl methylcellulose, microcrystalline cellulose, celluloseacetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (Veegum),and larch arabogalactan), alginates, polyethylene oxide, polyethyleneglycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes,water, alcohol, etc., and/or combinations thereof.

Exemplary preservatives include antioxidants, chelating agents,antimicrobial preservatives, antifungal preservatives, alcoholpreservatives, acidic preservatives, and other preservatives.

Exemplary antioxidants include alpha tocopherol, ascorbic acid, acorbylpalmitate, butylated hydroxyanisole, butylated hydroxytoluene,monothioglycerol, potassium metabisulfite, propionic acid, propylgallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, andsodium sulfite.

Exemplary chelating agents include ethylenediaminetetraacetic acid(EDTA) and salts and hydrates thereof (e.g., sodium edetate, disodiumedetate, trisodium edetate, calcium disodium edetate, dipotassiumedetate, and the like), citric acid and salts and hydrates thereof(e.g., citric acid monohydrate), fumaric acid and salts and hydratesthereof, malic acid and salts and hydrates thereof, phosphoric acid andsalts and hydrates thereof, and tartaric acid and salts and hydratesthereof. Exemplary antimicrobial preservatives include benzalkoniumchloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide,cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol,chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea,phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate,propylene glycol, and thimerosal.

Exemplary antifungal preservatives include butyl paraben, methylparaben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoicacid, potassium benzoate, potassium sorbate, sodium benzoate, sodiumpropionate, and sorbic acid.

Exemplary alcohol preservatives include ethanol, polyethylene glycol,phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate,and phenylethyl alcohol.

Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E,beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbicacid, sorbic acid, and phytic acid.

Other preservatives include tocopherol, tocopherol acetate, deteroximemesylate, cetrimide, butylated hydroxyanisol (BHA), butylatedhydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate (SLS),sodium lauryl ether sulfate (SLES), sodium bisulfite, sodiummetabisulfite, potassium sulfite, potassium metabisulfite, Glydant Plus,Phenonip, methylparaben, Germall 115, Germaben II, Neolone, Kathon, andEuxyl. In certain embodiments, the preservative is an anti-oxidant. Inother embodiments, the preservative is a chelating agent.

Exemplary buffering agents include citrate buffer solutions, acetatebuffer solutions, phosphate buffer solutions, ammonium chloride, calciumcarbonate, calcium chloride, calcium citrate, calcium glubionate,calcium gluceptate, calcium gluconate, D-gluconic acid, calciumglycerophosphate, calcium lactate, propanoic acid, calcium levulinate,pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasiccalcium phosphate, calcium hydroxide phosphate, potassium acetate,potassium chloride, potassium gluconate, potassium mixtures, dibasicpotassium phosphate, monobasic potassium phosphate, potassium phosphatemixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodiumcitrate, sodium lactate, dibasic sodium phosphate, monobasic sodiumphosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide,aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline,Ringer's solution, ethyl alcohol, etc., and combinations thereof.

Exemplary lubricating agents include magnesium stearate, calciumstearate, stearic acid, silica, talc, malt, glyceryl behanate,hydrogenated vegetable oils, polyethylene glycol, sodium benzoate,sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate,sodium lauryl sulfate, etc., and combinations thereof.

Exemplary oils include almond, apricot kernel, avocado, babassu,bergamot, black current seed, borage, cade, camomile, canola, caraway,carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee,corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed,geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate,jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademianut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange,orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed,pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood,sasquana, savoury, sea buckthorn, sesame, shea butter, silicone,soybean, sunflower, tea tree, thistle, tsubaki, vetiver, walnut, andwheat germ oils. Exemplary oils include, but are not limited to, butylstearate, caprylic triglyceride, capric triglyceride, cyclomethicone,diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil,octyldodecanol, oleyl alcohol, silicone oil, and combinations thereof.

Liquid dosage forms for oral and parenteral administration includepharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active ingredients,the liquid dosage forms may comprise inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed,groundnut, corn, germ, olive, castor, and sesame oils), glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid estersof sorbitan, and mixtures thereof. Besides inert diluents, the oralcompositions can include adjuvants such as wetting agents, emulsifyingand suspending agents, sweetening, flavoring, and perfuming agents. Incertain embodiments for parenteral administration, the conjugates of theinvention are mixed with solubilizing agents such as Cremophor,alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins,polymers, and combinations thereof.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions can be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation can be a sterile injectable solution,suspension or emulsion in a nontoxic parenterally acceptable diluent orsolvent, for example, as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that can be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a drug, it is often desirable to slowthe absorption of the drug from subcutaneous or intramuscular injection.This can be accomplished by the use of a liquid suspension ofcrystalline or amorphous material with poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolutionwhich, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally administered drugform is accomplished by dissolving or suspending the drug in an oilvehicle.

Compositions for rectal or vaginal administration are typicallysuppositories which can be prepared by mixing the conjugates of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active ingredient.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activeingredient is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may comprise buffering agents.

Solid compositions of a similar type can be employed as fillers in softand hard-filled gelatin capsules using such excipients as lactose ormilk sugar as well as high molecular weight polyethylene glycols and thelike. The solid dosage forms of tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally comprise opacifying agents and can be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions which can beused include polymeric substances and waxes. Solid compositions of asimilar type can be employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight polyethylene glycols and the like.

The active ingredients can be in micro-encapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active ingredient can be admixed with at least oneinert diluent such as sucrose, lactose or starch. Such dosage forms maycomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may comprise bufferingagents. They may optionally comprise opacifying agents and can be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions which can beused include polymeric substances and waxes.

Dosage forms for topical and/or transdermal administration of a compoundof this invention may include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants and/or patches. Generally, theactive ingredient is admixed under sterile conditions with apharmaceutically acceptable carrier and/or any needed preservativesand/or buffers as can be required. Additionally, the present inventioncontemplates the use of transdermal patches, which often have the addedadvantage of providing controlled delivery of an active ingredient tothe body. Such dosage forms can be prepared, for example, by dissolvingand/or dispensing the active ingredient in the proper medium.Alternatively or additionally, the rate can be controlled by eitherproviding a rate controlling membrane and/or by dispersing the activeingredient in a polymer matrix and/or gel.

Suitable devices for use in delivering intradermal pharmaceuticalcompositions described herein include short needle devices such as thosedescribed in U.S. Pat. Nos. 4,886,499; 5,190,521; 5,328,483; 5,527,288;4,270,537; 5,015,235; 5,141,496; and 5,417,662. Intradermal compositionscan be administered by devices which limit the effective penetrationlength of a needle into the skin, such as those described in PCTpublication WO 99/34850 and functional equivalents thereof. Jetinjection devices which deliver liquid vaccines to the dermis via aliquid jet injector and/or via a needle which pierces the stratumcorneum and produces a jet which reaches the dermis are suitable. Jetinjection devices are described, for example, in U.S. Pat. Nos.5,480,381; 5,599,302; 5,334,144; 5,993,412; 5,649,912; 5,569,189;5,704,911; 5,383,851; 5,893,397; 5,466,220; 5,339,163; 5,312,335;5,503,627; 5,064,413; 5,520,639; 4,596,556; 4,790,824; 4,941,880;4,940,460; and PCT publications WO 97/37705 and WO 97/13537. Ballisticpowder/particle delivery devices which use compressed gas to acceleratevaccine in powder form through the outer layers of the skin to thedermis are suitable. Alternatively or additionally, conventionalsyringes can be used in the classical mantoux method of intradermaladministration.

Formulations suitable for topical administration include, but are notlimited to, liquid and/or semi liquid preparations such as liniments,lotions, oil in water and/or water in oil emulsions such as creams,ointments and/or pastes, and/or solutions and/or suspensions.Topically-administrable formulations may, for example, comprise fromabout 1% to about 10% (w/w) active ingredient, although theconcentration of the active ingredient can be as high as the solubilitylimit of the active ingredient in the solvent. Formulations for topicaladministration may further comprise one or more of the additionalingredients described herein.

A pharmaceutical composition of the invention can be prepared, packaged,and/or sold in a formulation suitable for pulmonary administration viathe buccal cavity. Such a formulation may comprise dry particles whichcomprise the active ingredient and which have a diameter in the rangefrom about 0.5 to about 7 nanometers or from about 1 to about 6nanometers. Such compositions are conveniently in the form of drypowders for administration using a device comprising a dry powderreservoir to which a stream of propellant can be directed to dispersethe powder and/or using a self propelling solvent/powder dispensingcontainer such as a device comprising the active ingredient dissolvedand/or suspended in a low-boiling propellant in a sealed container. Suchpowders comprise particles wherein at least 98% of the particles byweight have a diameter greater than 0.5 nanometers and at least 95% ofthe particles by number have a diameter less than 7 nanometers.Alternatively, at least 95% of the particles by weight have a diametergreater than 1 nanometer and at least 90% of the particles by numberhave a diameter less than 6 nanometers. Dry powder compositions mayinclude a solid fine powder diluent such as sugar and are convenientlyprovided in a unit dose form.

Low boiling propellants generally include liquid propellants having aboiling point of below 65° F. at atmospheric pressure. Generally thepropellant may constitute 50 to 99.9% (w/w) of the composition, and theactive ingredient may constitute 0.1 to 20% (w/w) of the composition.The propellant may further comprise additional ingredients such as aliquid non-ionic and/or solid anionic surfactant and/or a solid diluent(which may have a particle size of the same order as particlescomprising the active ingredient).

Pharmaceutical compositions of the invention formulated for pulmonarydelivery may provide the active ingredient in the form of droplets of asolution and/or suspension. Such formulations can be prepared, packaged,and/or sold as aqueous and/or dilute alcoholic solutions and/orsuspensions, optionally sterile, comprising the active ingredient, andmay conveniently be administered using any nebulization and/oratomization device. Such formulations may further comprise one or moreadditional ingredients including, but not limited to, a flavoring agentsuch as saccharin sodium, a volatile oil, a buffering agent, a surfaceactive agent, and/or a preservative such as methylhydroxybenzoate. Thedroplets provided by this route of administration may have an averagediameter in the range from about 0.1 to about 200 nanometers.

The formulations described herein as being useful for pulmonary deliveryare useful for intranasal delivery of a pharmaceutical composition ofthe invention. Another formulation suitable for intranasaladministration is a coarse powder comprising the active ingredient andhaving an average particle from about 0.2 to 500 micrometers. Such aformulation is administered. by rapid inhalation through the nasalpassage from a container of the powder held close to the nares.

Formulations suitable for nasal administration may, for example,comprise from about as little as 0.1% (w/w) and as much as 100% (w/w) ofthe active ingredient, and may comprise one or more of the additionalingredients described herein. A pharmaceutical composition of theinvention can be prepared, packaged, and/or sold in a formulationsuitable for buccal administration. Such formulations may, for example,be in the form of tablets and/or lozenges made using conventionalmethods, and may contain, for example, 0.1 to 20% (w/w) activeingredient, the balance comprising an orally dissolvable and/ordegradable composition and, optionally, one or more of the additionalingredients described herein. Alternately, formulations suitable forbuccal administration may comprise a powder and/or an aerosolized and/oratomized solution and/or suspension comprising the active ingredient.Such powdered, aerosolized, and/or aerosolized formulations, whendispersed, may have an average particle and/or droplet size in the rangefrom about 0.1 to about 200 nanometers, and may further comprise one ormore of the additional ingredients described herein.

A pharmaceutical composition of the invention can be prepared, packaged,and/or sold in a formulation suitable for ophthalmic administration.Such formulations may, for example, be in the form of eye dropsincluding, for example, a 0.1/1.0% (w/w) solution and/or suspension ofthe active ingredient in an aqueous or oily liquid carrier. Such dropsmay further comprise buffering agents, salts, and/or one or more otherof the additional ingredients described herein. Otheropthalmically-administrable formulations which are useful include thosewhich comprise the active ingredient in microcrystalline form and/or ina liposomal preparation. Ear drops and/or eye drops are contemplated asbeing within the scope of this invention.

Although the descriptions of pharmaceutical compositions provided hereinare principally directed to pharmaceutical compositions which aresuitable for administration to humans, it will be understood by theskilled artisan that such compositions are generally suitable foradministration to animals of all sorts. Modification of pharmaceuticalcompositions suitable for administration to humans in order to renderthe compositions suitable for administration to various animals is wellunderstood, and the ordinarily skilled veterinary pharmacologist candesign and/or perform such modification with ordinary experimentation.General considerations in the formulation and/or manufacture ofpharmaceutical compositions can be found, for example, in Remington: TheScience and Practice of Pharmacy 21^(st) ed., Lippincott Williams &Wilkins, 2005.

Still further encompassed by the invention are pharmaceutical packsand/or kits. Pharmaceutical packs and/or kits provided may comprise aprovided composition and a container (e.g., a vial, ampoule, bottle,syringe, and/or dispenser package, or other suitable container). In someembodiments, provided kits may optionally further include a secondcontainer comprising a suitable aqueous carrier for dilution orsuspension of the provided composition for preparation of administrationto a subject. In some embodiments, contents of provided formulationcontainer and solvent container combine to form at least one unit dosageform.

In some embodiments, a provided composition of the invention can beuseful in conjunction with subject controlled analgesia (PCA) devices,wherein a subject can administer, for example, opioid analgesia asrequired for pain management.

Optionally, a single container may comprise one or more compartments forcontaining a provided composition, and/or appropriate aqueous carrierfor suspension or dilution. In some embodiments, a single container canbe appropriate for modification such that the container may receive aphysical modification so as to allow combination of compartments and/orcomponents of individual compartments. For example, a foil or plasticbag may comprise two or more compartments separated by a perforated sealwhich can be broken so as to allow combination of contents of twoindividual compartments once the signal to break the seal is generated.A pharmaceutical pack or kit may thus comprise such multi-compartmentcontainers including a provided composition and appropriate solventand/or appropriate aqueous carrier for suspension.

Optionally, instructions for use are additionally provided in such kitsof the invention. Such instructions may provide, generally, for example,instructions for dosage and administration. In other embodiments,instructions may further provide additional detail relating tospecialized instructions for particular containers and/or systems foradministration. Still further, instructions may provide specializedinstructions for use in conjunction and/or in combination withadditional therapy. In one non-limiting example, the formulations of theinvention can be used in conjunction with opioid analgesiaadministration, which may, optionally, comprise use of a subjectcontrolled analgesia (PCA) device. Thus, instructions for use ofprovided formulations may comprise instructions for use in conjunctionwith PCA administration devices.

III. Methods of Use and Treatment

The present invention provides methods for treating a FAAH-mediatedcondition comprising administering to a subject in need thereof atherapeutically effective amount of a compound of formula (I) or apharmaceutically acceptable form thereof.

The present invention also provides methods for inhibiting FAAH in asubject comprising administering to a subject in need thereof atherapeutically effective amount of a compound of formula (I) or apharmaceutically acceptable form thereof.

The present invention also provides a method of inhibiting activation ofthe FAAH pathway in vitro or ex vivo, comprising contacting a FAAHprotein with a compound of formula (I) in an amount sufficient to reducethe activation of the FAAH pathway.

The present invention also provides use of a compound of formula (I) forthe treatment of a FAAH-mediated condition in a subject.

The present invention also provides use of a compound of formula (I) inthe manufacture of a medicament. In certain embodiments, the medicamentis useful for treating a FAAH-mediated condition.

A “subject” to which administration is contemplated includes, but is notlimited to, humans (i.e., a male or female of any age group, e.g., apediatric subject (e.g, infant, child, adolescent) or adult subject(e.g., young adult, middle-aged adult or senior adult)) and/or otherprimates (e.g., cynomolgus monkeys, rhesus monkeys); mammals, includingcommercially relevant mammals such as cattle, pigs, horses, sheep,goats, cats, and/or dogs; and/or birds, including commercially relevantbirds such as chickens, ducks, geese, and/or turkeys.

As used herein, and unless otherwise specified, the terms “treat,”“treating” and “treatment” contemplate an action that occurs while asubject is suffering from the specified disease, disorder or condition,which reduces the severity of the disease, disorder or condition, orretards or slows the progression of the disease, disorder or condition.

As used herein, unless otherwise specified, the terms “prevent,”“preventing” and “prevention” contemplate an action that occurs before asubject begins to suffer from the specified disease, disorder orcondition, which inhibits or reduces the severity of the disease,disorder or condition.

As used herein, and unless otherwise specified, the terms “manage,”“managing” and “management” encompass preventing the recurrence of thespecified disease, disorder or condition in a subject who has alreadysuffered from the disease, disorder or condition, and/or lengthening thetime that a subject who has suffered from the disease, disorder orcondition remains in remission. The terms encompass modulating thethreshold, development and/or duration of the disease, disorder orcondition, or changing the way that a subject responds to the disease,disorder or condition.

As used herein, and unless otherwise specified, a “therapeuticallyeffective amount” of a compound is an amount sufficient to provide atherapeutic benefit in the treatment or management of a disease,disorder or condition, or to delay or minimize one or more symptomsassociated with the disease, disorder or condition. A therapeuticallyeffective amount of a compound means an amount of therapeutic agent,alone or in combination with other therapies, which provides atherapeutic benefit in the treatment or management of the disease,disorder or condition. The term “therapeutically effective amount” canencompass an amount that improves overall therapy, reduces or avoidssymptoms or causes of disease or condition, or enhances the therapeuticefficacy of another therapeutic agent.

As used herein, and unless otherwise specified, a “prophylacticallyeffective amount” of a compound is an amount sufficient to prevent adisease, disorder or condition, or one or more symptoms associated withthe disease, disorder or condition, or prevent its recurrence. Aprophylactically effective amount of a compound means an amount oftherapeutic agent, alone or in combination with other agents, whichprovides a prophylactic benefit in the prevention of the disease,disorder or condition. The term “prophylactically effective amount” canencompass an amount that improves overall prophylaxis or enhances theprophylactic efficacy of another prophylactic agent.

As used herein “inhibition”, “inhibiting”, “inhibit” and “inhibitor”,and the like, refer to the ability of a compound to reduce, slow, haltor prevent activity of a particular biological process (e.g., FAAHactivity) in a cell relative to vehicle.

“FAAH-mediated condition” as used herein, refers to a disease, disorderor condition which is treatable by inhibition of FAAH activity.“Disease”, “disorder” or “condition” are terms used interchangeablyherein. FAAH-mediated conditions include, but are not limited to,painful conditions, inflammatory conditions, immune disorders, disordersof the central nervous system, metabolic disorders, cardiac disordersand glaucoma.

In certain embodiments, the FAAH-mediated condition is a painfulcondition. As used herein, a “painful condition” includes, but is notlimited to, neuropathic pain (e.g., peripheral neuropathic pain),central pain, deafferentiation pain, chronic pain (e.g., chronicnociceptive pain, and other forms of chronic pain such as post-operativepain, e.g., pain arising after hip, knee, or other replacement surgery),pre-operative pain, stimulus of nociceptive receptors (nociceptivepain), acute pain (e.g., phantom and transient acute pain),non-inflammatory pain, inflammatory pain, pain associated with cancer,wound pain, burn pain, post-operative pain, pain associated with medicalprocedures, pain resulting from pruritus, painful bladder syndrome, painassociated with premenstrual dysphoric disorder and/or premenstrualsyndrome, pain associated with chronic fatigue syndrome, pain associatedwith pre-term labor, pain associated with drawl symptoms from drugaddiction, joint pain, arthritic pain (e.g., pain associated withcrystalline arthritis, osteoarthritis, psoriatic arthritis, goutyarthritis, reactive arthritis, rheumatoid arthritis or Reiter'sarthritis), lumbosacral pain, musculo-skeletal pain, headache, migraine,muscle ache, lower back pain, neck pain, toothache, dental/maxillofacialpain, visceral pain and the like.

One or more of the painful conditions contemplated herein can comprisemixtures of various types of pain provided above and herein (e.g.nociceptive pain, inflammatory pain, neuropathic pain, etc.). In someembodiments, a particular pain can dominate. In other embodiments, thepainful condition comprises two or more types of pains without onedominating. A skilled clinician can determine the dosage to achieve atherapeutically effective amount for a particular subject based on thepainful condition.

In certain embodiments, the painful condition is neuropathic pain. Theterm “neuropathic pain” refers to pain resulting from injury to a nerve.Neuropathic pain is distinguished from nociceptive pain, which is thepain caused by acute tissue injury involving small cutaneous nerves orsmall nerves in muscle or connective tissue. Neuropathic pain typicallyis long-lasting or chronic and often develops days or months followingan initial acute tissue injury. Neuropathic pain can involve persistent,spontaneous pain as well as allodynia, which is a painful response to astimulus that normally is not painful. Neuropathic pain also can becharacterized by hyperalgesia, in which there is an accentuated responseto a painful stimulus that usually is trivial, such as a pin prick.Neuropathic pain conditions can develop following neuronal injury andthe resulting pain may persist for months or years, even after theoriginal injury has healed. Neuronal injury may occur in the peripheralnerves, dorsal roots, spinal cord or certain regions in the brain.Neuropathic pain conditions include, but are not limited to, diabeticneuropathy (e.g., peripheral diabetic neuropathy); sciatica;non-specific lower back pain; multiple sclerosis pain; carpal tunnelsyndrome, fibromyalgia; HIV-related neuropathy; neuralgia (e.g.,post-herpetic neuralgia, trigeminal neuralgia); pain resulting fromphysical trauma (e.g., amputation; surgery, invasive medical procedures,toxins, burns, infection), pain resulting from cancer or chemotherapy(e.g., chemotherapy-induced pain such as chemotherapy-induced peripheralneuropathy), and pain resulting from an inflammatory condition (e.g., achronic inflammatory condition). Neuropathic pain can result from aperipheral nerve disorder such as neuroma; nerve compression; nervecrush, nerve stretch or incomplete nerve transsection; mononeuropathy orpolyneuropathy. Neuropathic pain can also result from a disorder such asdorsal root ganglion compression; inflammation of the spinal cord;contusion, tumor or hemisection of the spinal cord; tumors of thebrainstem, thalamus or cortex; or trauma to the brainstem, thalamus orcortex.

The symptoms of neuropathic pain are heterogeneous and are oftendescribed as spontaneous shooting and lancinating pain, or ongoing,burning pain. In addition, there is pain associated with normallynon-painful sensations such as “pins and needles” (paraesthesias anddysesthesias), increased sensitivity to touch (hyperesthesia), painfulsensation following innocuous stimulation (dynamic, static or thermalallodynia), increased sensitivity to noxious stimuli (thermal, cold,mechanical hyperalgesia), continuing pain sensation after removal of thestimulation (hyperpathia) or an absence of or deficit in selectivesensory pathways (hypoalgesia).

In certain embodiments, the painful condition is non-inflammatory pain.The types of non-inflammatory pain include, without limitation,peripheral neuropathic pain (e.g., pain caused by a lesion ordysfunction in the peripheral nervous system), central pain (e.g., paincaused by a lesion or dysfunction of the central nervous system),deafferentation pain (e.g., pain due to loss of sensory input to thecentral nervous system), chronic nociceptive pain (e.g., certain typesof cancer pain), noxious stimulus of nociceptive receptors (e.g., painfelt in response to tissue damage or impending tissue damage), phantompain (e.g., pain felt in a part of the body that no longer exists, suchas a limb that has been amputated), pain felt by psychiatric subjects(e.g., pain where no physical cause may exist), and wandering pain(e.g., wherein the pain repeatedly changes location in the body).

In certain embodiments, the painful condition is inflammatory pain. Incertain embodiments, the painful condition (e.g., inflammatory pain) isassociated with an inflammatory condition and/or an immune disorder.

In certain embodiments, the FAAH-mediated condition is an inflammatorycondition. The term “inflammatory condition” refers to those diseases,disorders or conditions that are characterized by signs of pain (dolor,from the generation of noxious substances and the stimulation ofnerves), heat (calor, from vasodilatation), redness (rubor, fromvasodilatation and increased blood flow), swelling (tumor, fromexcessive inflow or restricted outflow of fluid), and/or loss offunction (functio laesa, which can be partial or complete, temporary orpermanent. Inflammation takes on many forms and includes, but is notlimited to, acute, adhesive, atrophic, catarrhal, chronic, cirrhotic,diffuse, disseminated, exudative, fibrinous, fibrosing, focal,granulomatous, hyperplastic, hypertrophic, interstitial, metastatic,necrotic, obliterative, parenchymatous, plastic, productive,proliferous, pseudomembranous, purulent, sclerosing, seroplastic,serous, simple, specific, subacute, suppurative, toxic, traumatic,and/or ulcerative inflammation.

Exemplary inflammatory conditions include, but are not limited to,inflammation associated with acne, anemia (e.g., aplastic anemia,haemolytic autoimmune anaemia), asthma, arteritis (e.g., polyarteritis,temporal arteritis, periarteritis nodosa, Takayasu's arteritis),arthritis (e.g., crystalline arthritis, osteoarthritis, psoriaticarthritis, gouty arthritis, reactive arthritis, rheumatoid arthritis andReiter's arthritis), ankylosing spondylitis, amylosis, amyotrophiclateral sclerosis, autoimmune diseases, allergies or allergic reactions,atherosclerosis, bronchitis, bursitis, chronic prostatitis,conjunctivitis, Chagas disease, chronic obstructive pulmonary disease,cermatomyositis, diverticulitis, diabetes (e.g., type I diabetesmellitus, type 2 diabetes mellitus), a skin condition (e.g., psoriasis,eczema, burns, dermatitis, pruritus (itch)), endometriosis,Guillain-Barre syndrome, infection, ischaemic heart disease, Kawasakidisease, glomerulonephritis, gingivitis, hypersensitivity, headaches(e.g., migraine headaches, tension headaches), ileus (e.g.,postoperative ileus and ileus during sepsis), idiopathicthrombocytopenic purpura, interstitial cystitis (painful bladdersyndrome), gastrointestinal disorder (e.g., selected from peptic ulcers,regional enteritis, diverticulitis, gastrointestinal bleeding,eosinophilic gastrointestinal disorders (e.g., eosinophilic esophagitis,eosinophilic gastritis, eosinophilic gastroenteritis, eosinophiliccolitis), gastritis, diarrhea, gastroesophageal reflux disease (GORD, orits synonym GERD), inflammatory bowel disease (IBD) (e.g., Crohn'sdisease, ulcerative colitis, collagenous colitis, lymphocytic colitis,ischaemic colitis, diversion colitis, Behcet's syndrome, indeterminatecolitis) and inflammatory bowel syndrome (IBS)), lupus, multiplesclerosis, morphea, myeasthenia gravis, myocardial ischemia, nephroticsyndrome, pemphigus vulgaris, pernicious aneaemia, peptic ulcers,polymyositis, primary biliary cirrhosis, neuroinflammation associatedwith brain disorders (e.g., Parkinson's disease, Huntington's disease,and Alzheimer's disease), prostatitis, chronic inflammation associatedwith cranial radiation injury, pelvic inflammatory disease, reperfusioninjury, regional enteritis, rheumatic fever, systemic lupuserythematosus, schleroderma, scierodoma, sarcoidosis,spondyloarthopathies, Sjogren's syndrome, thyroiditis, transplantationrejection, tendonitis, trauma or injury (e.g., frostbite, chemicalirritants, toxins, scarring, burns, physical injury), vasculitis,vitiligo and Wegener's granulomatosis. In certain embodiments, theinflammatory disorder is selected from arthritis (e.g., rheumatoidarthritis), inflammatory bowel disease, inflammatory bowel syndrome,asthma, psoriasis, endometriosis, interstitial cystitis andprostatistis. In certain embodiments, the inflammatory condition is anacute inflammatory condition (e.g., for example, inflammation resultingfrom infection). In certain embodiments, the inflammatory condition is achronic inflammatory condition (e.g., conditions resulting from asthma,arthritis and inflammatory bowel disease). The compounds may also beuseful in treating inflammation associated with trauma andnon-inflammatory myalgia. The compounds may also be useful in treatinginflammation associated with cancer.

In certain embodiments, the FAAH-mediated condition is an immunedisorder. Immune disorders, such as auto-immune disorders, include, butare not limited to, arthritis (including rheumatoid arthritis,spondyloarthopathies, gouty arthritis, degenerative joint diseases suchas osteoarthritis, systemic lupus erythematosus, Sjogren's syndrome,ankylosing spondylitis, undifferentiated spondylitis, Behcet's disease,haemolytic autoimmune anaemias, multiple sclerosis, amyotrophic lateralsclerosis, amylosis, acute painful shoulder, psoriatic, and juvenilearthritis), asthma, atherosclerosis, osteoporosis, bronchitis,tendonitis, bursitis, skin condition (e.g., psoriasis, eczema, burns,dermatitis, pruritus (itch)), enuresis, eosinophilic disease,gastrointestinal disorder (e.g., selected from peptic ulcers, regionalenteritis, diverticulitis, gastrointestinal bleeding, eosinophilicgastrointestinal disorders (e.g., eosinophilic esophagitis, eosinophilicgastritis, eosinophilic gastroenteritis, eosinophilic colitis),gastritis, diarrhea, gastroesophageal reflux disease (GORD, or itssynonym GERD), inflammatory bowel disease (IBD) (e.g., Crohn's disease,ulcerative colitis, collagenous colitis, lymphocytic colitis, ischaemiccolitis, diversion colitis, Behcet's syndrome, indeterminate colitis)and inflammatory bowel syndrome (IBS)), and disorders ameliorated by agastroprokinetic agent (e.g., ileus, postoperative ileus and ileusduring sepsis; gastroesophageal reflux disease (GORD, or its synonymGERD); eosinophilic esophagitis, gastroparesis such as diabeticgastroparesis; food intolerances and food allergies and other functionalbowel disorders, such as non-ulcerative dyspepsia (NUD) and non-cardiacchest pain (NCCP, including costo-chondritis)).

In certain embodiments, the inflammatory disorder and/or the immunedisorder is a gastrointestinal disorder. In some embodiments, thegastrointestinal disorder is selected from gastrointestinal disorder(e.g., selected from peptic ulcers, regional enteritis, diverticulitis,gastrointestinal bleeding, eosinophilic gastrointestinal disorders(e.g., eosinophilic esophagitis, eosinophilic gastritis, eosinophilicgastroenteritis, eosinophilic colitis), gastritis, diarrhea,gastroesophageal reflux disease (GORD, or its synonym GERD),inflammatory bowel disease (IBD) (e.g., Crohn's disease, ulcerativecolitis, collagenous colitis, lymphocytic colitis, ischaemic colitis,diversion colitis, Behcet's syndrome, indeterminate colitis) andinflammatory bowel syndrome (IBS)). In certain embodiments, thegastrointestinal disorder is inflammatory bowel disease (IBD).

In certain embodiments, the inflammatory condition and/or immunedisorder is a skin condition. In some embodiments, the skin condition ispruritus (itch), psoriasis, eczema, burns or dermatitis. In certainembodiments, the skin condition is psoriasis. In certain embodiments,the skin condition is pruritis.

In certain embodiments, the FAAH-mediated condition is a disorder of thecentral nervous system (CNS) (“CNS disorder”). Exemplary CNS disordersinclude, but are not limited to, neurotoxicity and/or neurotrauma,stroke, multiple sclerosis, spinal cord injury, epilepsy, a mentaldisorder, a sleep condition, a movement disorder, nausea and/or emesis,amyotrophic lateral sclerosis, Alzheimer's disease and drug addiction.

In certain embodiments, the CNS disorder is neurotoxicity and/orneurotrauma, e.g., for example, as a result of acute neuronal injury(e.g., tramatic brain injury (TBI), stroke, epilepsy) or a chronicneurodegenerative disorder (e.g., multiple sclerosis, Parkinson'sdisease, Huntington's disease, amyotrophic lateral sclerosis,Alzheimer's disease). In certain embodiments, the compound of thepresent invention provides a neuroprotective effect, e.g., against anacute neuronal injury or a chronic neurodegenerative disorder.

In certain embodiments, the CNS disorder is stroke (e.g., ischemicstroke).

In certain embodiments, the CNS disorder is multiple sclerosis.

In certain embodiments, the CNS disorder is spinal cord injury.

In certain embodiments, the CNS disorder is epilepsy.

In certain embodiments, the CNS disorder is a mental disorder, e.g., forexample, depression, anxiety or anxiety-related conditions, a learningdisability or schizophrenia.

In certain embodiments, the CNS disorder is depression. “Depression,” asused herein, includes, but is not limited to, depressive disorders orconditions, such as, for example, major depressive disorders (e.g.,unipolar depression), dysthymic disorders (e.g., chronic, milddepression), bipolar disorders (e.g., manic-depression), seasonalaffective disorder, and/or depression associated with drug addiction(e.g., withdrawal). The depression can be clinical or subclinicaldepression. The depression can be associated with or premenstrualsyndrome and/or premenstrual dysphoric disorder.

In certain embodiments, the CNS disorder is anxiety. “Anxiety,” as usedherein, includes, but is not limited to anxiety and anxiety-relatedconditions, such as, for example, clinical anxiety, panic disorder,agoraphobia, generalized anxiety disorder, specific phobia, socialphobia, obsessive-compulsive disorder, acute stress disorder,post-traumatic stress disorder, adjustment disorders with anxiousfeatures, anxiety disorder associated with depression, anxiety disorderdue to general medical conditions, and substance-induced anxietydisorders, anxiety associated with drug addiction (e.g., withdrawal,dependence, reinstatement) and anxiety associated with nausea and/oremesis. This treatment may also be to induce or promote sleep in asubject (e.g., for example, a subject with anxiety).

In certain embodiments, the CNS disorder is a learning disorder (e.g.,attention deficit disorder (ADD)).

In certain embodiments, the CNS disorder is Schizophrenia.

In certain embodiments, the CNS disorder is a sleep condition. “Sleepconditions” include, but are not limited to, insomnia, narcolepsy, sleepapnea, restless legs syndrome (RLS), delayed sleep phase syndrome(DSPS), periodic limb movement disorder (PLMD), hypopnea syndrome, rapideye movement behavior disorder (RBD), shift work sleep condition (SWSD),and sleep problems (e.g., parasomnias) such as nightmares, nightterrors, sleep talking, head banging, snoring, and clenched jaw and/orgrinding of teeth (bruxism).

In certain embodiments, the CNS disorder is a movement disorder, e.g.,basal ganglia disorders, such as, for example, Parkinson's disease,levodopa-induced dyskinesia, Huntington's disease, Gilles de laTourette's syndrome, tardive diskinesia and dystonia.

In certain embodiments, the CNS disorder is Alzheimer's disease.

In certain embodiments, the CNS disorder is amyotrophic lateralsclerosis (ALS).

In certain embodiments, the CNS disorder is nausea and/or emesis.

In certain embodiments, the CNS disorder is drug addiction (e.g., forinstance, addiction to opiates, nicotine, cocaine, psychostimulants oralcohol).

In still yet other embodiments, the FAAH-mediated condition is a cardiacdisorder, e.g., for example, selected from hypertension, circulatoryshock, myocardial reperfusion injury and atherosclerosis.

In certain embodiments, the FAAH-mediated condition is a metabolicdisorder (e.g., a wasting condition, an obesity-related condition orcomplication thereof).

In certain embodiments, the metabolic disorder is a wasting condition. A“wasting condition,” as used herein, includes but is not limited to,anorexia and cachexias of various natures (e.g., weight loss associatedwith cancer, weight loss associated with other general medicalconditions, weight loss associated with failure to thrive, and thelike).

In certain embodiments, the metabolic disorder is an obesity-relatedcondition or a complication thereof. An “obesity-related condition” asused herein, includes, but is not limited to, obesity, undesired weightgain (e.g., from medication-induced weight gain, from cessation ofsmoking) and an over-eating disorder (e.g., binge eating, bulimia,compulsive eating, or a lack of appetite control each of which canoptionally lead to undesired weight gain or obesity). “Obesity” and“obese” as used herein, refers to class I obesity, class II obesity,class III obesity and pre-obesity (e.g., being “over-weight”) as definedby the World Health Organization.

Reduction of storage fat is expected to provide various primary and/orsecondary benefits in a subject (e.g., in a subject diagnosed with acomplication associated with obesity) such as, for example, an increasedinsulin responsiveness (e.g., in a subject diagnosed with Type IIdiabetes mellitus); a reduction in elevated blood pressure; a reductionin elevated cholesterol levels; and/or a reduction (or a reduced risk orprogression) of ischemic heart disease, arterial vascular disease,angina, myocardial infarction, stroke, migraines, congestive heartfailure, deep vein thrombosis, pulmonary embolism, gall stones,gastroesophagael reflux disease, obstructive sleep apnea, obesityhypoventilation syndrome, asthma, gout, poor mobility, back pain,erectile dysfunction, urinary incontinence, liver injury (e.g., fattyliver disease, liver cirrhosis, alcoholic cirrhosis, endotoxin mediatedliver injury) or chronic renal failure. Thus, the method of thisinvention is applicable to obese subjects, diabetic subjects, andalcoholic subjects.

In some embodiments, treatment of an obesity-related condition orcomplication thereof involves reduction of body weight in the subject.In some embodiments, treatment of an obesity-related condition orcomplication thereof involves appetite control in the subject.

In other embodiments, the FAAH-mediated condition is glaucoma.

IV. Administration

Provided compounds can be administered using any amount and any route ofadministration effective for treatment. The exact amount required willvary from subject to subject, depending on the species, age, and generalcondition of the subject, the severity of the infection, the particularcomposition, its mode of administration, its mode of activity, and thelike.

Compounds provided herein are typically formulated in dosage unit formfor ease of administration and uniformity of dosage. It will beunderstood, however, that the total daily usage of the compositions ofthe present invention will be decided by the attending physician withinthe scope of sound medical judgment. The specific therapeuticallyeffective dose level for any particular subject or organism will dependupon a variety of factors including the disease, disorder, or conditionbeing treated and the severity of the disorder; the activity of thespecific active ingredient employed; the specific composition employed;the age, body weight, general health, sex and diet of the subject; thetime of administration, route of administration, and rate of excretionof the specific active ingredient employed; the duration of thetreatment; drugs used in combination or coincidental with the specificactive ingredient employed; and like factors well known in the medicalarts.

The compounds and compositions provided herein can be administered byany route, including oral, intravenous, intramuscular, intra-arterial,intramedullary, intrathecal, subcutaneous, intraventricular,transdermal, interdermal, rectal, intravaginal, intraperitoneal, topical(as by powders, ointments, creams, and/or drops), mucosal, nasal, bucal,enteral, sublingual; by intratracheal instillation, bronchialinstillation, and/or inhalation; and/or as an oral spray, nasal spray,and/or aerosol. Specifically contemplated routes are systemicintravenous injection, regional administration via blood and/or lymphsupply, and/or direct administration to an affected site. In general themost appropriate route of administration will depend upon a variety offactors including the nature of the agent (e.g., its stability in theenvironment of the gastrointestinal tract), the condition of the subject(e.g., whether the subject is able to tolerate oral administration),etc.

The exact amount of a compound required to achieve a therapeuticallyeffective amount will vary from subject to subject, depending, forexample, on species, age, and general condition of a subject, severityof the side effects or disorder, identity of the particular compound(s),mode of administration, and the like. The desired dosage can bedelivered three times a day, two times a day, once a day, every otherday, every third day, every week, every two weeks, every three weeks, orevery four weeks. In certain embodiments, the desired dosage can bedelivered using multiple administrations (e.g., two, three, four, five,six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, ormore administrations).

In certain embodiments, a therapeutically effective amount of a compoundfor administration one or more times a day to a 70 kg adult human maycomprise about 0.0001 mg to about 3000 mg, about 0.0001 mg to about 2000mg, about 0.0001 mg to about 1000 mg, about 0.001 mg to about 1000 mg,about 0.01 mg to about 1000 mg, about 0.1 mg to about 1000 mg, about 1mg to about 1000 mg, about 1 mg to about 100 mg, about 10 mg to about1000 mg, or about 100 mg to about 1000 mg, of an inventive compound perunit dosage form. It will be appreciated that dose ranges as describedherein provide guidance for the administration of providedpharmaceutical compositions to an adult. The amount to be administeredto, for example, a child or an adolescent can be determined by a medicalpractitioner or person skilled in the art and can be lower or the sameas that administered to an adult.

It will be also appreciated that a compound or composition, as describedherein, can be administered in combination with one or more additionaltherapeutically active agents. The compound or composition can beadministered concurrently with, prior to, or subsequent to, one or moreadditional therapeutically active agents. In general, each agent will beadministered at a dose and/or on a time schedule determined for thatagent. In will further be appreciated that the additionaltherapeutically active agent utilized in this combination can beadministered together in a single composition or administered separatelyin different compositions. The particular combination to employ in aregimen will take into account compatibility of the inventive compoundwith the additional therapeutically active agent and/or the desiredtherapeutic effect to be achieved. In general, it is expected thatadditional therapeutically active agents utilized in combination beutilized at levels that do not exceed the levels at which they areutilized individually. In some embodiments, the levels utilized incombination will be lower than those utilized individually.

The compounds or compositions can be administered in combination withagents that improve their bioavailability, reduce and/or modify theirmetabolism, inhibit their excretion, and/or modify their distributionwithin the body. It will also be appreciated that therapy employed mayachieve a desired effect for the same disorder (for example, a compoundcan be administered in combination with an anti-inflammatory,anti-anxiety and/or anti-depressive agent, etc.), and/or it may achievedifferent effects (e.g., control of adverse side-effects).

Exemplary active agents include, but are not limited to, anti-canceragents, antibiotics, anti-viral agents, anesthetics, anti-coagulants,inhibitors of an enzyme, steroidal agents, steroidal or non-steroidalanti-inflammatory agents, antihistamine, immunosuppressant agents,anti-neoplastic agents, antigens, vaccines, antibodies, decongestants,sedatives, opioids, pain-relieving agents, analgesics, anti-pyretics,hormones, prostaglandins, progestational agents, anti-glaucoma agents,ophthalmic agents, anti-cholinergics, anti-depressants, anti-psychotics,hypnotics, tranquilizers, anti-convulsants/anti-epileptics (e.g.,Neurontin, Lyrica, valproates (e.g., Depacon), and otherneurostabilizing agents), muscle relaxants, anti-spasmodics, musclecontractants, channel blockers, miotic agents, anti-secretory agents,anti-thrombotic agents, anticoagulants, anti-cholinergics, β-adrenergicblocking agents, diuretics, cardiovascular active agents, vasoactiveagents, vasodilating agents, anti-hypertensive agents, angiogenicagents, modulators of cell-extracellular matrix interactions (e.g. cellgrowth inhibitors and anti-adhesion molecules), orinhibitors/intercalators of DNA, RNA, protein-protein interactions,protein-receptor interactions, etc. Active agents include small organicmolecules such as drug compounds (e.g., compounds approved by the Foodand Drugs Administration as provided in the Code of Federal Regulations(CFR)), peptides, proteins, carbohydrates, monosaccharides,oligosaccharides, polysaccharides, nucleoproteins, mucoproteins,lipoproteins, synthetic polypeptides or proteins, small molecules linkedto proteins, glycoproteins, steroids, nucleic acids, DNAs, RNAs,nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides,lipids, hormones, vitamins and cells.

In certain embodiments, the additional therapeutically active agent is apain-relieving agent. Exemplary pain relieving agents include, but arenot limited to, analgesics such as non-narcotic analgesics [e.g.,salicylates such as aspirin, ibuprofen (MOTRIN®, ADVIL®), ketoprofen(ORUDIS®), naproxen (NAPROSYN®), acetaminophen, indomethacin] ornarcotic analgesics [e.g., opioid analgesics such as tramadol, fentenyl,sufentanil, morphine, hydromorphone, codeine, oxycodone, andbuprenorphine]; non-steroidal anti-inflammatory agents (NSAIDs) [e.g.,aspirin, acetaminophen, COX-2 inhibitors]; steroids or anti-rheumaticagents; migraine preparations such as beta adrenergic blocking agents,ergot derivatives; tricyclic antidepressants (e.g., amitryptyline,desipramine, imipramine); anti-epileptics (e.g., clonaxepam, valproicacid, phenobarbital, phenyloin, tiagaine, gabapentin, carbamazepine,topiramate, sodium valproate); α₂ agonists; selective serotonin reuptakeinhibitors (SSRIs), selective norepinepherine uptake inhibitors;benzodiazepines; mexiletine (MEXITIL); flecamide (TAMBOCOR); NMDAreceptor antagonists [e.g., ketamine, detromethorphan, methadone]; andtopical agents [e.g., capsaicin (Zostrix), EMLA cream, lidocaine,prilocaine].

In other embodiments, the additional therapeutically active agent is ananti-inflammatory agent. Exemplary anti-inflammatory agents include, butare not limited to, aspirin; ibuprofen; ketoprofen; naproxen; etodolac)(LODINE®); COX-2 inhibitors such as celecoxib (CELEBREX®), rofecoxib(VIOXX®), valdecoxib (BEXTRA®, parecoxib, etoricoxib (MK663), deracoxib,2-(4-ethoxy-phenyl)-3-(4-methanesulfonyl-phenyl)-pyrazolo[1,5-b]pyridazine,4-(2-oxo-3-phenyl-2,3-dihydrooxazol-4-yl)benzenesulfonamide,darbufelone, flosulide,4-(4-cyclohexyl-2-methyl-5-oxazolyl)-2-fluorobenzenesulfonamide),meloxicam, nimesulide,1-Methylsulfonyl-4-(1,1-dimethyl-4-(4-fluorophenyl)cyclopenta-2,4-dien-3-yl)_(b)enzene,4-(1,5-Dihydro-6-fluoro-7-methoxy-3-(trifluoromethyl)-(2)-benzothiopyrano(4,3-c)pyrazol-1-yl)benzenesulfonamide,4,4-dimethyl-2-phenyl-3-(4-methylsulfonyl)phenyl)cyclo-butenone,4-Amino-N-(4-(2-fluoro-5-trifluoromethyl)-thiazol-2-yl)-benzenesulfonamide,1-(7-tert-butyl-2,3-dihydro-3,3-dimethyl-5-benzo-furanyl)-4-cyclopropylbutan-1-one, or their physiologically acceptable salts, esters orsolvates; sulindac (CLINORIL®); diclofenac (VOLTAREN®); piroxicam(FELDENE®); diflunisal (DOLOBID®), nabumetone (RELAFEN®), oxaprozin(DAYPRO®), indomethacin)(INDOCIN®); or steroids such as PEDIAPED®prednisolone sodium phosphate oral solution, SOLU-MEDROL®methylprednisolone sodium succinate for injection, PRELONE® brandprednisolone syrup.

Further examples of anti-inflammatory agents include naproxen, which iscommercially available in the form of EC-NAPROSYN® delayed releasetablets, NAPROSYN®, ANAPROX® and ANAPROX® DS tablets and NAPROSYN®suspension from Roche Labs, CELEBREX® brand of celecoxib tablets, VIOXX®brand of rofecoxib, CELESTONE® brand of betamethasone, CUPRAMINE® brandpenicillamine capsules, DEPEN® brand titratable penicillamine tablets,DEPO-MEDROL brand of methylprednisolone acetate injectable suspension,ARAVA™ leflunomide tablets, AZULFIDIINE EN-tabs® brand of sulfasalazinedelayed release tablets, FELDENE® brand piroxicam capsules, CATAFLAM®diclofenac potassium tablets, VOLTAREN® diclofenac sodium delayedrelease tablets, VOLTAREN®-XR diclofenac sodium extended releasetablets, or ENBREL® etanerecept products.

V. Methods of Determining Biological Activity

Methods of determining the activity of the compounds provided herein forvarious therapeutic uses are known in the art. These include, but arenot limited to, high throughput screening to identify compounds thatbind to and/or modulate the activity of isolated FAAH, as well as invitro and in vivo models of therapies.

Assays useful for screening the compounds provided herein may detect thebinding of the inhibitor to FAAH or the release of a reaction product(e.g., fatty acid amide or ethanolamine) produced by the hydrolysis of asubstrate such as oleoylethanolamide or ananadamide. The substrate canbe labeled to facilitate detection of the released reaction products.U.S. Pat. No. 5,559,410 discloses high throughput screening methods forproteins, and U.S. Pat. Nos. 5,576,220 and 5,541,061 disclose highthroughput methods of screening for ligand/antibody binding.

Methods for screening FAAH inhibitors for an antinociceptive effect areknown in the art. For example, compounds can tested in the mousehot-plate test and the mouse formalin test, and the nociceptivereactions to thermal or chemical tissue damage measured (for example,see U.S. Pat. No. 6,326,156 for a description of methods of screeningfor antinociceptive activity; see also Cravatt et al. Proc. Natl. Acad.Sci. U.S.A. (2001) 98:9371-9376).

Two pharmacologically validated animal models of anxiety are theelevated zero maze test, and the isolation-induced ultrasonic emissiontest. The zero maze consists of an elevated annular platform with twoopen and two closed quadrants and is based on the conflict between ananimal's instinct to explore its environment and its fear of open spaces(see, for example, Bickerdike, M. J. et al., Eur. J. Pharmacol., (994)271, 403-411; Shepherd, J. K. et al., Psychopharmacology, (1994) 116,56-64). Clinically used anxiolytic drugs, such as the benzodiazepines,increase the proportion of time spent in, and the number of entries madeinto, the open compartments.

A second test for an anti-anxiety compound is the ultrasonicvocalization emission model, which measures the number of stress-inducedvocalizations emitted by rat pups removed from their nest (see, forexample, Insel, T. R. et al., Pharmacol. Biochem. Behav., 24, 1263-1267(1986); Miczek, K. A. et al., Psychopharmacology, 121, 38-56 (1995);Winslow, J. T. et al., Biol. Psychiatry, 15, 745-757 (1991).

The effect of the compounds provided herein in the treatment ofdepression can be tested in the model of chronic mild stress inducedanhedonia in rats. This model is based on the observation that chronicmild stress causes a gradual decrease in sensitivity to rewards, forexample consumption of sucrose, and that this decrease isdose-dependently reversed by chronic treatment with antidepressants.See, e.g., Willner, Paul, Psychopharmacology, 1997, 134, 319-329.

Another test for antidepressant activity is the forced swimming test(Nature 266, 730-732, 1977). In this test, animals are administered anagent 30 or 60 minutes before being placed in container of water, andthe time during which they remain immobile is recorded. A decrease inthe immobility time of the mice is indicative of antidepressantactivity.

A similar test for antidepressant activity is the mouse caudalsuspension test (Psychopharmacology, 85, 367-370, 1985). In this test,animals are administered an agent 30 or 60 minutes before beingsuspended by the tail, and their immobility time is recorded. A decreasein the immobility time of the mice is indicative of antidepressantactivity.

Animal models are available for assessing anticonvulsant activity oftest compounds (see, e.g., U.S. Pat. Nos. 6,309,406 and 6,326,156).

Inhibition of FAAH has been reported to induce sleep in test animals(see, e.g., U.S. Pat. No. 6,096,784). Methods for studying sleepinducing compounds are known in the art (see, e.g., U.S. Pat. Nos.6,096,784 and 6,271,015). Compounds can be administered to a test animal(e.g., rat or mouse) or a human and the subsequent time (e.g., onset,duration) spent sleeping (e.g., eyes closed, motor quiescence) can bemonitored. See also WO 98/24396.

Methods for screening FAAH inhibitors which induce catalepsy are alsowell known in the art (see, e.g., Quistand et al. in Toxicology andApplied Pharmacology 173: 48-55 (2001); Cravatt et al. Proc. Natl. Acad.Sci. U.S.A. 98:9371-9376 (2001)).

Methods of assessing appetitive behavior are known in the art (see,e.g., U.S. Pat. No. 6,344,474). One method of assessing the effect onappetite behavior is to administer a FAAH inhibitor to a rat and assessits effect on the intake of a sucrose solution (see, e.g., W. C. Lynchet al., Physiol. Behav., 1993, 54, 877-880).

Two pharmacologically validated animal models of neuropathic pain arethe rat spinal nerve ligation model (Chung model) and a rat model ofchemotherapy-induced neuropathic pain. After establishing neuropathy inthese models, as a measure of mechanical allodynia, paw withdrawalthresholds were measured by stimulation with von Frey filaments (see,for example, Kim S H and Chung J M, Pain (1992) 50, 355-63;Nozaki-Taguchi N, et al., Pain (2001) 93, 69-76). Clinically usedneuropathic pain drugs, such as the Gabapentin (Neurontin), increase thepaw withdrawal threshold from stimulation with von Frey filaments.

Two pharmacologically validated animal models of inflammatory andmechanical pain are a joint compression model in rats treated withadjuvant or agents that produce joint degeneration. Treatment withclinically used anti-inflammatory agents such as naproxen increases thethreshold of behavioral response to joint compression (see, for example,Wilson A W, et al., Eur. J. Pain (2006) 10, 537-49; Ivanavicius S A, etal., Pain (2007) 128, 272-282).

A pharmacologically validated animal models of cancer pain is mousemodel where implantation in the calcaneus bone of fibrosarcoma cellsproduces paw hyperalgesia. Treatment with clinically used analgesicsagents such as morphine increases the threshold of behavioral responseto mechanical algesia (see, for example, Khasabova, et al., J.Neurscience (2008) 28, 11141-52).

EXEMPLIFICATION

The invention now being generally described, it will be more readilyunderstood by reference to the following examples, which are includedmerely for purposes of illustration of certain aspects and embodimentsof the present invention, and are not intended to limit the invention.

General Synthetic Methods Method 1

General conditions for the preparation of 3-bromo-isoxazolines: Alkene(1.2 equiv) and potassium hydrogen carbonate (2.5 equiv) are suspendedin ethyl acetate (0.40 M with respect to alkene).N,N-Dibromoformaldoxime (1.0 equiv) is added and the reaction wasallowed to stir at 23° C. for 14-28 h. Upon completion as judged by thinlayer chromatography analysis, the reaction was split between water andtert-butyl methyl ether, and the organic layer was washed with water andbrine, dried over sodium sulfate, and concentrated in vacuo. Theconcentrated reaction mixture was purified by flash silica gelchromatography (ethyl acetate/hexanes) to provide the desired3-bromo-isoxazoline.

Method 2

General conditions for the preparation of 3-bromo-isoxazolines: A flaskis charged with glyoxylic acid monohydrate (1.0 equiv) and hydroxylaminehydrochloride (1.1 equiv). The mixture was dissolved in water (2.0 Mwith respect to glyoxylic acid monohydrate) and stirred at 23° C. for 24h. The mixture was diluted with water and extracted with ethyl acetate.The organic layer was dried over sodium sulfate and concentrated toprovide the desired crude oxime which was used directly in subsequentcycloaddition. The resulting oxime (1.1 equiv) from the first step issuspended in a 3:1 mixture of dimethoxyethane:water (v/v) (0.15 M withrespect to oxime) and cooled to 0° C. N—Bromosuccinamide (NBS) (2.0equiv) was added and the reaction was allowed to stir at 23° C. for 20min. The resulting mixture is then added to a solution of alkene (1.0equiv) and potassium bicarbonate (2.5 equiv) in dimethoxyethane (1.50 Mwith respect to alkene) and the reaction is allowed to stir for 20 h at23° C. Upon completion as judged by thin layer chromatography analysis,the reaction was split between water and tert-butyl methyl ether, andthe organic layer was washed with brine, dried over sodium sulfate, andconcentrated in vacuo. The concentrated reaction mixture was purified byflash silica gel chromatography (ethyl acetate/hexanes) to provide thedesired 3-bromo-isoxazoline.

Method 3

General conditions for the preparation of 3-aryloxy-isoxazolines or3-heteroaryloxy-isoxazolines: A microwave reaction vial is charged witha given 3-bromo-isoxazoline (1.0 equiv) and an alcohol (e.g., a phenolor a hydroxypyridine) (3.0 equiv) and dissolved in N-methylpyrrolidine(0.50 M with respect to isoxazoline). Crushed sodium hydroxide (2.0equiv) is added and the mixture was sealed and heated in a microwavereaction at 150° C. for 30 min. The reaction was then split betweenwater and tert-butyl methyl ether, and the organic layer was washed withbrine, dried over sodium sulfate, and concentrated in vacuo. Theconcentrated reaction mixture was purified by flash silica gelchromatography (ethyl acetate/hexanes) to provide the desiredisoxazoline.

Method 4

General conditions for the preparation of 3-aryloxy-isoxazolines or3-heteroaryloxy-isoxazolines: A flask is charged with a given3-bromo-isoxazoline (1.0 equiv) and the alcohol (e.g., a phenol or ahydroxypyridine) (2.0 equiv) and dissolved in N,N-dimethylforamide (0.4M with respect to isoxazoline). Sodium hydride (2.0 equiv) is added andthe reaction is allowed to stir for 10 min until all of the gasevolution ceases. The reaction is then heated to 150° C. for 1-5 h.After the reaction is determine to be complete by thin layerchromatography analysis, the reaction was then split between water andethyl acetate, and the organic layer was washed with 1N NaOH and brine,and then dried over sodium sulfate, and concentrated in vacuo. Theconcentrated reaction mixture was purified by flash silica gelchromatography (ethyl acetate/hexanes) to provide the desiredisoxazoline.

Method 5

General conditions for the preparation of 3-aryloxy-isoxazolines: Aflask is charged with a given 3-bromo-isoxazoline (1.0 equiv) and thealcohol (e.g., a phenol or a hydroxypyridine) (2.0 equiv) and dissolvedin N,N-dimethylforamide or N-methylpyrrolidinone (0.15 M with respect toisoxazole). Cesium carbonate (1.2 to 3 equiv) is added and the reactionis heated to 120° C. in an oil bath for 1 h. The reaction was then splitbetween water and tert-butyl methyl ether, and the organic layer waswashed with brine, dried over sodium sulfate, and concentrated in vacuo.The concentrated reaction mixture was purified by flash silica gelchromatography (methanol/methylene chloride) to provide the desiredisoxazoline.

Method 6

General conditions for the preparation of alkenes: under a nitrogenatmosphere, 0.25 M methyltriphenylphosphonium bromide (1.1 equiv)dissolved in tetrahydrofuran was cooled to 0° C. after which the mixturewas treated drop wise with sodium hexamethyldisilazane (NaHMDS) intetrahydrofuran (1.0 M, 1.2 equiv). After stirring an additional 30 minat 0° C., a given aldehyde or ketone is added and the reaction isallowed to warm slowly to 23° C. overnight. The mixture was quenchedsaturated ammonium chloride and concentrated to remove thetetrahydrofuran. The mixture was then diluted with water and extractedwith ethyl acetate. The organic layer was washed with brine, dried oversodium sulfate and concentrated in vacuo. The concentrated reactionmixture was purified by flash silica gel chromatography (ethylacetate/hexanes) to provide the desired alkene.

Method 7

General conditions for the preparation of alkenes: under a nitrogenatmosphere, 0.15 M methyltriphenylphosphonium bromide (1.5 equiv)dissolved in tetrahydrofuran was cooled to −78° C. after which themixture was treated drop wise with n-butyl lithium in hexanes (2.5 M,1.5 equiv). After stirring an additional 1 h at −78° C., a givenaldehyde or ketone is added and the reaction is allowed to warm slowlyto 23° C. overnight. The mixture was quenched saturated ammoniumchloride and concentrated to remove the tetrahydrofuran. The mixture wasthen diluted with water and extracted with ethyl acetate. The organiclayer was washed with brine, dried over sodium sulfate and concentratedin vacuo. The concentrated reaction mixture was purified by flash silicagel chromatography (ethyl acetate/hexanes) to provide the desiredalkene.

Method 8

General conditions for the preparation of alkenes: under a nitrogenatmosphere, 0.12 M methyltriphenylphosphonium bromide (2.5 equiv) wasdissolved in tetrahydrofuran after which potassium tert-butoxide (4.0equiv) was added in six portions. After stirring an additional 1 h at23° C., a given aldehyde or ketone is added and the reaction was heatedto 55° C. for 2 h. The mixture was quenched saturated ammonium chlorideand concentrated to remove the tetrahydrofuran. The mixture was thenacidified to pH 5-6 with 1N HCl and extracted with methylene chloride.The organic layer was washed with brine and then dried over sodiumsulfate and concentrated in vacuo. The concentrated reaction mixture waspurified by flash silica gel chromatography (ethyl acetate/hexanes) toprovide the desired alkene.

Method 9

General conditions for the preparation of styrenes: a dry flask underargon atmosphere was charged with aryl bromide (1.0 equiv), potassiumvinyltrifluoroborate (1.2 equiv),1,1″-bis(diphenylphosphino)-ferrocenedichloropalladium(II) methylenechloride adduct (0.02 equiv) and triethylamine (1.0 equiv) and themixture was suspended in isopropanol (0.25 M with respect to arylbromide) and heated at 80° C. for 2-24 h. The mixture was then dilutedwith water and extracted with diethyl ether. The organic layer waswashed with brine and then dried over magnesium sulfate and concentratedin vacuo. The concentrated reaction mixture was purified by flash silicagel chromatography (ethyl acetate/hexanes) to provide the desiredstyrene.

Method 10

General conditions for the preparation of styrenes: a dry flask under anitrogen atmosphere was charged with aryl bromide (1.0 equiv),tributylvinyltin (1.1 equiv) and dissolved in toluene (0.3 M withrespect to bromide). The resulting mixture was further purged withnitrogen for 10 min after which tetrakis(triphenyphosphine)palladium(0.1 equiv) was added and the reaction was refluxed for 1.5 h. After thereaction was determined to be complete by TLC analysis, it was allowedto cool and loaded directly onto a silica gel column where it waspurified by flash silica gel chromatography (ethyl acetate/hexanes) toprovide the desired styrene.

Method 11

General conditions for the hydrolysis of pyridyl and pyrimidinyl boronicacids to their corresponding phenols: A flask is charged with a givenboronic acid or ester thereof (1.0 equiv) and dissolved intetrahydrofuran (1.1 M, 10 volumes). Sodium perborate (1.0 equiv) isdissolved in water (1.1 M with respect to boronic acid, 10 volumes) andsonicated for 10 min. The perborate suspension is then added to the THFsolution using tetrahydrofuran (1.6 volumes) to rinse the remainingsolid perborate into the reaction mixture. The reaction is allowed tostir at room temperature (reaction is mildly exothermic) after whichammonium chloride is added in three portions (10 equiv) and the reactioncooled back down to room temperature. After 40 min, the reaction wasconcentrated under vacuum until all of the tetrahydrofuran was removed.The resulting solid was collected by vacuum filtration, washed withexcess waster and dried in a vacuum oven for 40° C. for 3d to providethe desired phenol in 80% yield.

Chiral HPLC Method

Enantiomeric or diastereomeric mixtures of compounds can be separatedusing known methods, including chiral high pressure liquidchromatography (HPLC) and chiral supercritical fluid chromatography(SFC). Exemplary chiral columns found useful in separating such mixturesof compounds of the present invention include, but are not limited to,ChiralPak® AD-H, ChiralPak® OD-H, ChiralPak® AY, RegisPack™, and S,SWhelkO®-1 and LUX™ Cellulose2 columns. One or more of these columns wereused to separate enantiomeric mixtures of compounds of the presentinvention in order to obtain substantially enantiomerically purecompounds.

Synthesis of Exemplary Compounds of Formula I

Syntheses of exemplary compounds are set forth below. Compounds wereassayed as inhibitors of human FAAH using the method described in detailin Example 32. Activity designated as “A” refers to compounds having aK_(i) of less than or equal to 100 nM, “B” refers to compounds having aK_(i) of between 100 nM and 1 microM, and “C” refers to compounds havinga K_(i) of greater than or equal to 1 microM.

Example 1

3-bromo-4,5-dihydroisoxazole II-1a and II-1b were prepared in 1 stepfrom 4-vinylpyridine using Method 2. These compounds can be separatedusing chiral HPLC methods known in the art. For example, see chiral HPLCMethod disclosed herein. [M−H]—=226.0 m/z. Activity: C

Example 2

3-bromo-4,5-dihydroisoxazole II-2a and II-2b were was prepared in 1 stepfrom 3-vinylpyridine using Method 2. These compounds can be separatedusing chiral HPLC methods known in the art. For example, see chiral HPLCMethod disclosed herein. [M−H]−=226.0 m/z. Activity: C

Example 3

3-bromo-4,5-dihydroisoxazole II-3a and II-3b were prepared in 1 stepfrom 2-vinylpyridine using Method 2. These compounds can be separatedusing chiral HPLC methods known in the art. For example, see chiral HPLCMethod disclosed herein. [M−H]−=226.0 m/z. Activity: C

Example 4

3-bromo-4,5-dihydroisoxazole II-4a and II-4-b were prepared in 2 stepsstarting with alkene formation from 1-phenyl-1H-pyrazole-4-carbaldehydeusing Method 8 followed by cycloaddition using Method 2. These compoundscan be separated using chiral HPLC methods known in the art. Forexample, see chiral HPLC Method disclosed herein. [M−H]−=291.0 m/z.Activity: B

Example 5

3-bromo-4,5-dihydroisoxazole II-5a and II-5b were prepared in 2 stepsstarting with alkene formation from 2-phenyl-1,3-thiazole-4-carbaldehydeusing Method 8 followed by cycloaddition using Method 2. These compoundscan be separated using chiral HPLC methods known in the art. Forexample, see chiral HPLC Method disclosed herein. [M−H]−=308.0 m/z.Activity: C

Example 6

3-bromo-4,5-dihydroisoxazole II-6a and II-6b were prepared in 2 stepsstarting with alkene formation from 2-phenyl-1,3-thiazole-5-carbaldehydeusing Method 8 followed by cycloaddition using Method 1. These compoundscan be separated using chiral HPLC methods known in the art. Forexample, see chiral HPLC Method disclosed herein. [M−H]−=308.0 m/z.Activity: A

Example 7

3-bromo-4,5-dihydroisoxazole II-7a and II-7b were prepared in 2 stepsstarting with alkene formation from 5-phenylthiophene-2-carbaldehydeusing Method 8 followed by cycloaddition using Method 1. These compoundscan be separated using chiral HPLC methods known in the art. Forexample, see chiral HPLC Method disclosed herein. [M+H]+=309.6 m/z.Activity: A

Example 8

3-bromo-4,5-dihydroisoxazole II-8a and II-8b were prepared in 2 stepsstarting with alkene formation from 4-phenylthiophene-2-carbaldehydeusing Method 8 followed by cycloaddition using Method 2. These compoundscan be separated using chiral HPLC methods known in the art. Forexample, see chiral HPLC Method disclosed herein. [M−H]−=307.0 m/z.Activity: A

Example 9

3-bromo-4,5-dihydroisoxazole II-9a and II-9b were prepared in 2 stepsstarting with alkene formation from 6-quinolinecarbaldehyde using Method8 followed by cycloaddition using Method 2. These compounds can beseparated using chiral HPLC methods known in the art. For example, seechiral HPLC Method disclosed herein. [M−H]−=276.0 m/z. Activity: A

Example 10

3-bromo-4,5-dihydroisoxazole II-10a and II-10b were prepared in 2 stepsstarting with alkene formation from 3-quinolinecarbaldehyde using Method8 followed by cycloaddition using Method 2. These compounds can beseparated using chiral HPLC methods known in the art. For example, seechiral HPLC Method disclosed herein. [M−H]−=276.0 m/z. Activity: A

Example 11

3-bromo-4,5-dihydroisoxazole II-11a and II-11b were prepared in 2 stepsstarting with alkene formation from 6-bromoquinoxaline using Method 10followed by cycloaddition using Method 2. These compounds can beseparated using chiral HPLC methods known in the art. For example, seechiral HPLC Method disclosed herein. [M−H]−=277.0 m/z. Activity: A

Example 12

3-bromo-4,5-dihydroisoxazole II-12a and II-12b were prepared in 2 stepsstarting with alkene formation from 5-bromo-1-methyl-1H-indole usingMethod 9 followed by cycloaddition using Method 2. These compounds canbe separated using chiral HPLC methods known in the art. For example,see chiral HPLC Method disclosed herein. [M−H]−=278.0 m/z. Activity: A

Example 13

3-bromo-4,5-dihydroisoxazole II-13a and II-13b were prepared in 2 stepsstarting with the Boc-protection of 2-amino-6-bromobenzothiazole asfollows: The benzothiazole (1.0 equiv) is dissolved in methylenechloride (0.12 M with respect to thiazole). Di-tert-butyl dicarbonate(3.0 equiv) is then added followed by the addition of DMAP (0.20 equiv)in five portions. The reaction was allowed to stir for 2 h at 23° C.after which point there was no more SM by TLC analysis. The reaction wasquenched with the addition of methanol (75 equiv) and allowed to stirfor 10 min after which the reaction was split between water andmethylene chloride, and the organic layer was washed with 0.5 M citricacid solution (2×) and saturated sodium bicarbonate solution (1×), driedover magnesium sulfate, and concentrated in vacuo to provide a crudesolid which was converted directly to the desired3-bromo-4,5-dihydroisoxazole using Method 9 followed by Method 2. Thesecompounds can be separated using chiral HPLC methods known in the art.For example, see chiral HPLC Method disclosed herein. [M−H]−=397.0 m/z.Activity: B

Example 14

1-Allylpiperazine is dissolved in methylene chloride (1.1 M with respectto piperazine). Potassium carbonate (1.5 equiv) was added followed bydi-tert-butyl dicarbonate (1.1 equiv). The reaction was allowed to stirfor 16 h after which it was then split between water and tert-butylmethyl ether, and the organic layer was washed with brine, dried oversodium sulfate, and concentrated in vacuo to provide crude alkene whichwas directly converted to the desired 3-bromo-4,5-dihydroisoxazoleII-14a and II-14b in 1 step using Method 1. These compounds can beseparated using chiral HPLC methods known in the art. For example, seechiral HPLC Method disclosed herein. [M−H]−=347.1 m/z. Activity: A

Example 15

3-bromo-4,5-dihydroisoxazole II-15a and II-15b were prepared in 2 stepsstarting with alkene formation from benzyl4-formylpiperidine-1-carboxylate using Method 8 followed bycycloaddition using Method 2. These compounds can be separated usingchiral HPLC methods known in the art. For example, see chiral HPLCMethod disclosed herein. [M−H]−=366.1 m/z. Activity: B

Example 16

3-bromo-4,5-dihydroisoxazole II-16a and II-16b were prepared in 2 stepsstarting with alkene formation from tent-butyl4-formylpiperidine-1-carboxylate using Method 8 followed bycycloaddition using Method 2. These compounds can be separated usingchiral HPLC methods known in the art. For example, see chiral HPLCMethod disclosed herein. [M−H]−=332.1 m/z. Activity: A

Example 17

3-bromo-4,5-dihydroisoxazole II-17a and II-17b were prepared in 2 stepsstarting with alkene formation from2-(4-chlorophenyl)thiazole-5-carbaldehyde using Method 8 followed bycycloaddition using Method 1. These compounds can be separated usingchiral HPLC methods known in the art. For example, see chiral HPLCMethod disclosed herein. [M+H]+=342.5 m/z. Activity: A

Example 18

3-bromo-4,5-dihydroisoxazole II-18a and II-18b were prepared in 2 stepsstarting with alkene formation from 1-(2-phenylthiazol-5-yl)ethanoneusing Method 8 followed by cycloaddition using Method 1. These compoundscan be separated using chiral HPLC methods known in the art. Forexample, see chiral HPLC Method disclosed herein. [M+H]+=322.3 m/z.Activity: A

Example 19

3-bromo-4,5-dihydroisoxazole II-19a and II-19b were prepared in 2 stepsstarting with alkene formation from 2-phenylthiazole-5-carbaldehydeusing Method 8 except that ethyltriphenylphosphoium bromide was used inplace of methyltriphenylphosphoium bromide followed by cycloadditionusing Method 1. [M+H]+=325.1 m/z. Activity: A

Example 20

3-bromo-4,5-dihydroisoxazole II-20a and II-20b were isolated as thetrans diastereomers which also formed during the cycloaddition inExample 19. These compounds can be separated using chiral HPLC methodsknown in the art. For example, see chiral HPLC Method disclosed herein.[M+H]+=324.9 m/z. Activity: C

Example 21

3-(pyridin-3-yloxy)-4,5-dihydroisoxazole II-21a and II-21b were preparedin 1 step from racemic compound II-6 and 3-hydroxypyridine using Method5. These compounds can be separated using chiral HPLC methods known inthe art. For example, see chiral HPLC Method disclosed herein.[M+H]+=325.1 m/z. Activity: A

Example 22

3-(pyridin-3-yloxy)-4,5-dihydroisoxazole II-22a and II-22b were preparedin 1 step from racemic compound II-18 and 5-hydroxyprimidine usingMethod 5. These compounds can be separated using chiral HPLC methodsknown in the art. For example, see chiral HPLC Method disclosed herein.[M+H]+=340.4 m/z. Activity: A

Example 23

3-(pyridin-3-yloxy)-4,5-dihydroisoxazole II-23a and II-23b were preparedin 1 step from racemic compound II-18 and 3-hydroxypyridine using Method5. These compounds can be separated using chiral HPLC methods known inthe art. For example, see chiral HPLC Method disclosed herein.[M+H]+=339.3 m/z. Activity: A

Example 24

3-bromo-4,5-dihydroisoxazole II-24a and II-24b were prepared in 2 stepsstarting with alkene formation from1-(4-methyl-2-phenylthiazol-5-yl)ethanone using Method 8 followed bycycloaddition using Method 1. These compounds can be separated usingchiral HPLC methods known in the art. For example, see chiral HPLCMethod disclosed herein. [M+H]+=339.0 m/z. Activity: B

Example 25

3-bromo-4,5-dihydroisoxazole II-25a and II-25b were prepared in 2 stepsstarting with alkene formation from5-pyridin-3-ylthiophen-2-carbaldehyde using Method 8 followed bycycloaddition using Method 1. These compounds can be separated usingchiral HPLC methods known in the art. For example, see chiral HPLCMethod disclosed herein. [M+H]+=310.3 m/z. Activity: A

Example 26

3-(pyrimidin-5-yloxy)-4,5-dihydroisoxazole II-26a and II-26b wereprepared in 1 step from racemic compound II-25 and 5-hydroxypyrimidineusing Method 5. These compounds can be separated using chiral HPLCmethods known in the art. For example, see chiral HPLC Method disclosedherein. [M+H]+=325.1 m/z. Activity: A

Example 27

3-(pyridin-3-yloxy)-4,5-dihydroisoxazole II-27a and II-27b were preparedin 2 steps from racemic compound II-25 according to the followingprocedure: 5-hydroxypicolinic acid methyl ester was reacted using Method5 followed by methyl ester hydrolysis. The methyl ester of racemic3-(pyridin-3-yloxy)-4,5-dihydroisoxazole II-27 (1.0 equiv) was dissolvedin 1:1 tetrahydrofuran/water (0.06 M) and lithium hydroxide (8.0 equiv)was added. The reaction was allowed to stir at room temperature for 1 hafter which point the tetrahydrofuran was removed under a stream ofnitrogen and the remaining solution was acidified to pH<2 with 1N HCl toprovide desired acid II-27a and II-27b as a white solid which wasisolated via vacuum filtration. These compounds can be separated usingchiral HPLC methods known in the art. For example, see chiral HPLCMethod disclosed herein. [M+H]+=367.5 m/z. Activity: A

Example 28

3-(pyridin-3-yloxy)-4,5-dihydroisoxazole II-28a and II-28b were preparedin 2 steps from racemic compound II-6 by first reacting II-6 with6-(methylthio)pyridin-3-ol (prepared from6-(methylthio)pyridin-3-ylboronic acid using Method 11) using Method 5followed by oxidation according to the following procedure: racemic3-(6-(methylthio)pyridin-3-yloxy)-4,5-dihydroisoxazole was dissolved inmethylene chloride (0.5 M with respect to isoxazole) after which pointm-chloroperbenzoic acid (2.0 equiv) was added in 1 portion and thereaction was allowed to stir at room temperature for 1 h. After thereaction was determined to be complete by LC/MS, the solvent wasevaporated. The crude mixture was then redissolved in tert-butylmethylether (0.5 M) after which hexane was slowly added until a solidprecipitated. The solid was then collected via vacuum filtration andwashed with 1:1 hexanes/MTBE to provide the desired3-(pyridin-3-yloxy)-4,5-dihydroisoxazole II-29a and II-29b as a whitesolid. These compounds can be separated using chiral HPLC methods knownin the art. For example, see chiral HPLC Method disclosed herein.[M+H]+=404.1 m/z. Activity: A

Example 29

3-(pyridin-3-yloxy)-4,5-dihydroisoxazole II-29a and II-29b were preparedin 2 steps from racemic compound II-18 by first reacting II-18 with6-(methylthio)pyridin-3-ol (prepared from6-(methylthio)pyridin-3-ylboronic acid using Method 11) using Method 5followed by oxidation under analogous conditions to Example 28. Thesecompounds can be separated using chiral HPLC methods known in the art.For example, see chiral HPLC Method disclosed herein. [M+H]+=417.9 m/z.Activity: A

Example 30

2-(4,5-dihydroisoxazol-3-ylamino)alcohol II-30a and II-30b were preparedin 1 step according to the following procedure: racemic3-bromo-4,5-dihydroisoxazole 1-8 (1.0 equiv) was dissolved in n-butanol(0.64 M) followed by the addition of (S)-2-amino-1-phenylethanol (1.2equiv) and sodium carbonate (2.5 equiv). The reaction is the sealed andheated in an oil bath to 120° C. for 18 h after which it allowed to cooland then transferred to a separatory funnel with excess water andtert-butylmethyl ether. The aqueous layer was washed withtert-butylmethyl ether (2×) and the combined organic layers were washedwith brine, dried over magnesium sulfate and concentrate to provide aorange solid that was purified using flash silica gel chromatography(gradient toluene/hexanes to toluene/ethyl acetate) to provide racemicII-30 as a white solid. These compounds can be separated using chiralHPLC methods known in the art. For example, see chiral HPLC Methoddisclosed herein. [M+H]+=374.20 m/z. Activity: C

Example 31

2-(4,5-dihydroisoxazol-3-ylamino)alcohol II-31a and II-31b were preparedusing the analogous procedure as Example 30 except that(R)-2-amino-1-phenylethanol was used in place of(S)-2-amino-1-phenylethanol. These compounds can be separated usingchiral HPLC methods known in the art. For example, see chiral HPLCMethod disclosed herein. [M+H]+=366.4 m/z. Activity: C

Example 32 Inhibition of Human FAAH

Human FAAH Preparation: COS-7 cells were split the day before, 1:5 into150 mm×25 mm cell culture dishes (Corning Inc., Cat. No. 430599).Transient transfection took place at 30-40% confluency according toFuGENE 6 Transfection Reagent (Roche, Cat. No. 11814 443 001).

Transfection Procedure: The FuGENE transfection 6 reagent (45 uL) wasadded to 1410 μL of media (DMEM, serum free without pen/strep) in a 15mL conical tube and incubated at room temp for 5 minutes, followed bythe addition of FAAH plasmid DNA (15 μg) (OriGene Cat. No. TC119221,Genbank Accession No. NM 001441.1, 0.67 ug/uL) and a further incubationof 15 minutes at room temperature. The resulting solution was added intoone dish of 30-40% confluent COS-7 cells in a drop-wise manner. TheCOS-7 cell dish was subsequently incubated for 48 hours. The cells arethen harvested.

Harvest procedure: Media was aspirated from the dishes and the cellsrinsed with 10 mL PBS. The PBS was removed and 3 mL of PBS added to thedish. The dish was scraped to resuspend the cells, and the subsequentcell suspension collected into a 15 mL conical tube. The cells werepelleted by centrifugation at 1200 rpm for 5 minutes in a bench topcentrifuge. PBS was removed and the cell pellet snap frozen in liquidnitrogen and stored at −80° C.

COS-7 Cells—FAAH Purification:

-   -   (1) Fractionation: Frozen cell pellets from transient        transfections were thawed on ice and resuspended in 12.5 mM        Hepes pH 8.0, 100 mM NaCl, 1 mM EDTA (10 mL/0.2 g cell pellet).        The pellets were dounce homogenized and then sonicated to        produce cell extract. The cell extract was subsequently        centrifuged at 1000 g to remove cellular debris. The pellet was        discarded and the supernatant centrifuged at 13,000 g for 20        minutes. The pellet contained membrane bound FAAH. The        supernatant was discarded and the pellet resolubilized.    -   (2) Re-solubilization: The fraction of interest, (13,000 g,        membrane fraction) was re-suspended in 2.3 mL re-suspension        buffer (20 mM Hepes pH 7.8, 10% v/v Glycerol, 1 mM EDTA, 1%        Triton X-100) and the sample incubated on ice for 1 hour and        then centrifuged to remove any particulate matter. The        supernatant containing solubilized human FAAH was aliquoted and        snap frozen in liquid nitrogen and stored at −80° C. until use.    -   (3) Characterization: Protein Concentration determined by        Bradford assay.        -   SDS gel and Western blot to confirm presence of FAAH        -   FAAH activity assay        -   K_(m) determination—96-well assay        -   Linear dependence—96-well assay        -   Standard compound Ki determination—384-well assay

Human FAAH assay; Experimental Protocol: A 0.1 mg/mL Human FAAH solutionwas made up in FAAH reaction buffer, and 24 ul pipeted into a 384 wellplate. To this was added 1 μL of a 3 fold serially diluted inhibitorfrom a DMSO stock solution. The FAAH solution and inhibitor wereincubated for 30 minutes at room temperature. The FAAH reaction wasinitiated by the addition of 25 μL of 40 μM AMC Arachidonoyl Amide inFAAH reaction buffer, yielding a final reaction human FAAH preparationconcentration of 0.05 mg/ml and AMC-Arachidonoyl substrate concentrationof 20 μM, reaction volume 50 μL. The reaction was allowed to proceed for4 hours at room temperature. The reaction was stopped by the addition of25 μL 12 μM a-ketoheterocycle (Cayman Chemicals, catalogue # 10435). Themicrotiter plate was read in the envision plate reader.

The raw fluorescence was plotted on the y axis and the inhibitorconcentration on the x axis to give a dose response inhibition curve.The data was fitted to a single site competitive inhibition equation,fixing the Km for the human enzyme to 12 μM and 9 μM respectively.

Other assays which can be used to determine the inhibition of FAAH bythe compounds of the present invention include: (1) a fluorescence-basedassay for fatty acid amide hydrolase compatible with high-throughputscreening as described in Manjunath et al., Analytical Biochemistry(2005) 343:143-151; and (2) a high-throughput screening for thediscovery of inhibitors of fatty acid amide hydrolase using amicrosome-based fluorescent assay. Wang et al., Biomolecular Screening(2006) 1-9.

Example 33 Evidence for Covalent Complex Formation Between Serine-241 ofFAAH and Isoxazolines

Treatment of rat FAAH protein with the active site-directed irreversibleinhibitor methoxy arachidonyl fluorophosphonate results in a crystalstructure wherein methoxy arachidonyl phosphonate is covalently bound tothe side chain of Ser-241 (Bracey et al., Science (2002) 298:1793-1796).

Based on this data, it is hypothesized that the isoxazoline compounds ofthe present invention form covalent complexes with the nucleophilic sidechain of Ser-241. This hypothesis is consistent with the kinetic data,with the proposed binding involving nucleophilic attack of theisoxazoline electrophile by the active site Ser-241, resulting in theelimination of the leaving group from the cytosolic port, and thesubsequent formation of a covalent enzyme-isoxazoline adduct. Recoveryof activity would subsequently involve a deacylation reaction, whichwould occur inefficiently, if at all, for the covalentenzyme-isoxazoline adduct.

Recovery of activity experiments were performed via a jump dilutionmethod which involved rapidly diluting the enzyme-inhibitor complex5-fold below its apparent Ki, and measuring activity as a function oftime. Little or no enzyme activity was regained over a period of twohours, indicating essentially irreversible inhibition, or a very slowlyhydrolysable complex, supporting the above hypothesis.

Other Embodiments

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents to the specificembodiments of the invention described herein. Such equivalents areintended to be encompassed by the following claims.

1. A compound of formula (I):

or a pharmaceutically acceptable form thereof, wherein: each of R^(a),R^(b), and R^(c) independently is selected from —H, C₁₋₁₀ alkyl andC₁₋₁₀ perhaloalkyl, R^(d) is the group -L-Z, and Z is selected from 3-14membered heterocyclyl and 5-14 membered heteroaryl; L is a covalent bondor a divalent C₁₋₆ hydrocarbon group, wherein one, two or threemethylene units of L are optionally and independently replaced with oneor more oxygen, sulfur or nitrogen atoms; G is selected from —CN, —NO₂,—S(═O)R^(e), —SO₂R^(e), —SO₂NR^(f)R^(e), —PO₂R^(e), —PO₂OR^(e),—PO₂NR^(f)R^(e), —(C═O)R^(e), —(C═O)OR^(e), —(C═O)NR^(f)R^(e), —Br, —I,—F, —Cl, —OR^(e), —ONR^(f)R^(e), —ONR^(f)(C═O)R^(e), —ONR^(f)SO₂R^(e),—ONR^(f)PO₂R^(e), —ONR^(f)PO₂OR^(e), —SR^(e), —OSO₂R^(e),—NR^(f)SO₂R^(e), —OPO₂R^(e), —OPO₂OR^(e), —NR^(f)PO₂R^(e),—NR^(f)PO₂OR^(e), —OPO₂NR^(f)R^(e), —O(C═O)R^(e), —O(C═O)OR^(e),—NR^(f)R^(e), —NR^(f)(C═O)R^(e), —NR^(f)(C═O)OR^(e), —O(C═O)NR^(f)R^(e),—NR^(f)(C═NR^(f))NR^(f)R^(e), —O(C═NR^(f))NR^(f)R^(e),—NR^(f)(C═NR^(f))OR^(e), —[N(R^(f))₂R^(e)]⁺X⁻ wherein X⁻ is acounterion; and each R^(e) is selected from C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl,C₂₋₁₀ alkynyl, C₃₋₁₀ carbocycyl, C₆₋₁₄ aryl, 3-14 membered heterocyclyland 5-14 membered heteroaryl; each R^(f) attached to a nitrogen atom is,independently, selected from —H, C₁₋₁₀ alkyl, or an amino protectinggroup; or R^(e) and R^(f) are joined to form an 3-14 memberedheterocyclyl ring or an 5-14 membered heteroaryl ring.
 2. The compoundaccording to claim 1, wherein L is a covalent bond or L is a divalentC₁₋₆ hydrocarbon group, wherein one, two or three methylene units of Lare replaced with one or more oxygen atoms.
 3. The compound according toclaim 2, wherein L is a covalent bond.
 4. The compound according toclaim 2, wherein L is an unsubstituted divalent C₁₋₆ hydrocarbon group,wherein one methylene unit of L is replaced with an oxygen atom.
 5. Thecompound claim 2, wherein L is —O—.
 6. The compound according to claim1, wherein R^(a), R^(b), and R^(c) independently is selected from —H,C₁₋₃ alkyl and C₁₋₃ perhaloalkyl.
 7. The compound according to claim 6,wherein each R^(a), R^(b), and R^(c) is independently selected from —H,—CH₃ and —CF₃.
 8. The compound according to claim 7, wherein R^(a) andR^(b) are —H and R^(c) is selected from —CH₃ and —CF₃.
 9. The compoundaccording to claim 7, wherein R^(b) and R^(c) are —H and R^(a) isselected from —CH₃ and —CF₃.
 10. The compound according to claim 7,wherein each of R^(a), R^(b), and R^(c) is —H.
 11. The compoundaccording to claim 1, wherein Z is a 5-membered heteroaryl.
 12. Thecompound according to claim 11, wherein the compound is of the formula:

or a pharmaceutically acceptable form thereof; wherein Y¹, Y², Y³ and Y⁴are, independently, selected from CH, CR¹⁵, O, S, N, or NR¹⁸, with theproviso that at least one of Y¹, Y², Y³ and Y⁴ are selected from O, S,N, or NR¹⁸; and each R¹⁵ is independently selected from fluoro (—F),bromo (—Br), chloro (—Cl), and iodo (—I), —CN, —NO₂, —N₃, —SO₂H, —SO₃H,—OH, —OR¹⁶, —ON(R¹⁸)₂, —N(R¹⁸)₂, —N(R¹⁸)₃ ⁺X⁻, —N(OR¹⁷)R¹⁸, —SH, —SR¹⁶,—SSR¹⁷, —C(═O)R¹⁶, —CO₂H, —CHO, —C(OR¹⁷)₂, —CO₂R¹⁶, —OC(═O)R¹⁶,—OCO₂R¹⁶, —C(═O)N(R¹⁸)₂, —OC(═O)N(R¹⁸)₂, —NR¹⁸C(═O)R¹⁶,—NR¹⁸C(═O)N(R¹⁸)₂, —C(═NR¹⁸)R¹⁶, —C(═NR¹⁸)OR¹⁶, —OC(═NR¹⁸)R¹⁶,—OC(—NR¹⁸)OR¹⁶, —C(═NR¹⁸)N(R¹⁸)₂, —OC(═NR¹⁸)N(R¹⁸)₂,—NR¹⁸C(═NR¹⁸)N(R¹⁸)₂, —C(═O)NR¹⁸SO₂R¹⁶, —NR¹⁸SO₂R¹⁶, —SO₂N(R¹⁸)₂,—SO₂R¹⁶, —SO₂OR¹⁶, —OSO₂R¹⁶, —S(═O)R¹⁶, —OS(═O)R¹⁶, —Si(R¹⁶)₃,—OSi(R¹⁶)₃—C(═S)N(R¹⁸)₂, —C(═O)SR¹⁶, —C(═S)SR¹⁶, —SC(S)SR¹⁶, —P(═O)₂R¹⁶,—OP(═O)₂R¹⁶, —P(═O)(R¹⁶)₂, —OP(═O)(R¹⁶)₂, —OP(═O)(OR¹⁷)₂,—P(═O)₂N(R¹⁸)₂, —OP(═O)₂N(R¹⁸)₂, —P(═O)(NR¹⁸)₂, —OP(═O)(NR¹⁸)₂,—NR¹⁸P(═O)(OR¹⁷)₂, —NR¹⁸P(═O)(NR¹⁸)₂, —P(R¹⁷)₂, —P(R¹⁷)₃, —OP(R¹⁷)₂,—OP(R¹⁷)₃, —B(OR¹⁷)₂, —BR¹⁶(OR¹⁷), C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl,C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₄ carbocyclyl, 3-14 memberedheterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroaryl, wherein eachalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroarylis independently substituted with 0, 1, 2, 3, 4, or 5 R¹⁹ groups; or twovicinal R¹⁵ groups are replaced with the group —O(C(R²)₂)₁₋₂O— whereineach R² is independently —H, C₁₋₆ alkyl or halogen; each instance of R¹⁶is, independently, selected from C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocyclyl, 3-14 membered heterocyclyl,C₆₋₁₄ aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl,alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl isindependently substituted with 0, 1, 2, 3, 4, or 5 R¹⁹ groups; eachinstance of R¹⁸ is, independently, selected from hydrogen, —OH, —OR¹⁶,—N(R¹⁷)₂, —C(═O)R¹⁶, —C(═O)N(R¹⁷)₂, —CO₂R¹⁶, —SO₂R¹⁶, —C(═NR¹⁷)OR¹⁶,—C(═NR¹⁷)N(R¹⁷)₂, —SO₂N(R¹⁷)₂, —SO₂R¹⁷, —SO₂OR¹⁷, —SOR¹⁶, —C(═S)N(R¹⁷)₂,—C(═O)SR¹⁷, —C(═S)SR¹⁷, —P(═O)₂R¹⁶, —P(═O)(R¹⁶)₂, —P(═O)₂N(R¹⁷)₂,—P(═O)(NR¹⁷)₂, C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, C₃₋₁₀ carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and5-14 membered heteroaryl, or two R¹⁷ groups attached to an N atom arejoined to form a 3-14 membered heterocyclyl or 5-14 membered heteroarylring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl,aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or5 R¹⁹ groups; each instance of R¹⁷ is, independently, selected fromhydrogen, C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl,C₃₋₁₀ carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14membered heteroaryl, or two R¹⁷ groups attached to an N atom are joinedto form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring,wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl,and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R¹⁹groups; each instance of R¹⁹ is, independently, selected from halogen,—CN, —NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR²⁰, —ON(R²¹)₂, —N(R²¹)₂, —N(R²¹)₃⁺X⁻, —N(OR²⁰)R²¹, —SH, —SR^(N), —SSR²⁰, —C(═O)R²⁰, —CO₂H, —CO₂R²⁰,—OC(═O)R²⁰, —OCO₂R²⁰, —C(═O)N(R²¹)₂, —OC(═O)N(R²¹)₂, —NR²¹C(═O)R²⁰,—NR²¹CO₂R²⁰, —NR²¹C(═O)N(R²¹)₂, —C(═NR²¹)OR²⁰, —OC(═NR²¹)R²⁰,—OC(═NR²¹)OR²⁰, —C(═NR²¹)N(R²¹)₂, —OC(═NR²¹)N(R²¹)₂,—NR²¹C(═NR²¹)N(R²¹)₂, —NR²¹SO₂R²⁰, —SO₂N(R²¹)₂, —SO₂R²⁰, —SO₂OR²⁰,—OSO₂R²⁰, —S(═O)R²⁰, —Si(R²⁰)₃, —OSi(R²⁰)₃, —C(═S)N(R²¹)₂, —C(═O)SR²⁰,—C(═S)SR²⁰, —SC(═S)SR²⁰, —P(═O)₂R²⁰, —P(═O)(R²⁰)₂, —OP(═O)(R²⁰)₂,—OP(═O)(OR²⁰)₂, C₁₋₆ alkyl, C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ carbocyclyl, 3-10 membered heterocyclyl, C₆₋₁₀ aryl, 5-10membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl,heterocyclyl, aryl, and heteroaryl is independently substituted with 0,1, 2, 3, 4, or 5 R²² groups, or two geminal R¹⁹ substituents can bejoined to form ═O or ═S; each instance of R²⁰ is, independently,selected from C₁₋₆ alkyl, C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₁₀ carbocyclyl, C₆₋₁₀ aryl, 3-10 membered heterocyclyl, and 3-10membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl,heterocyclyl, aryl, and heteroaryl is independently substituted with 0,1, 2, 3, 4, or 5 R²² groups; each instance of R²¹ is, independently,selected from hydrogen, C₁₋₆ alkyl, C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl, 3-10 membered heterocyclyl, C₆₋₁₀ aryland 5-10 membered heteroaryl, or two R²¹ groups attached to an N atomare joined to form a 3-14 membered heterocyclyl or 5-14 memberedheteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl,heterocyclyl, aryl, and heteroaryl is independently substituted with 0,1, 2, 3, 4, or 5 R²² groups; and each instance of R²² is, independently,halogen, —CN, —NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OC₁₋₆ alkyl, —ON(C₁₋₆alkyl)₂, —N(C₁₋₆ alkyl)₂, —N(C₁₋₆ alkyl)₃X, —NH(C₁₋₆ alkyl)₂X, —NH₂(C₁₋₆alkyl)X, —NH₃X, —N(OC₁₋₆ alkyl)(C₁₋₆ alkyl), —N(OH)(C₁₋₆ alkyl),—NH(OH), —SH, —SC₁₋₆ alkyl, —SS(C₁₋₆ alkyl), —C(═O)(C₁₋₆ alkyl), —CO₂H,—CO₂(C₁₋₆ alkyl), —OC(═O)(C₁₋₆ alkyl), —OCO₂(C₁₋₆ alkyl), —C(═O)NH₂,—C(═O)N(C₁₋₆ alkyl)₂, —OC(═O)NH(C₁₋₆ alkyl), —NHC(═O)(C₁₋₆ alkyl),—N(C₁₋₆ alkyl)C(═O)(C₁₋₆ alkyl), —NHCO₂(C₁₋₆ alkyl), —NHC(═O)N(C₁₋₆alkyl)₂, —NHC(═O)NH(C₁₋₆ alkyl), —NHC(═O)NH₂, —C(═NH)O(C₁₋₆ alkyl),—OC(═NH)(C₁₋₆ alkyl), —OC(═NH)OC₁₋₆ alkyl, —C(═NH)N(C₁₋₆ alkyl)₂,—C(═NH)NH(C₁₋₆ alkyl), —C(═NH)NH₂, —OC(═NH)N(C₁₋₆ alkyl)₂,—OC(NH)NH(C₁₋₆ alkyl), —OC(NH)NH₂, —NHC(NH)N(C₁₋₆ alkyl)₂, —NHC(═NH)NH₂,—NHSO₂ (C₁₋₆ alkyl), —SO₂N(C₁₋₆ alkyl)₂, —SO₂NH(C₁₋₆ alkyl), —SO₂NH₂,—SO₂C₁₋₆ alkyl, —SO₂OC₁₋₆ alkyl, —OSO₂C₁₋₆ alkyl, —SOC₁₋₆ alkyl,—Si(C₁₋₆ alkyl)₃, —OSi(C₁₋₆ alkyl)₃ —C(═S)N(C₁₋₆ alkyl)₂, C(═S)NH(C₁₋₆alkyl), C(═S)NH₂, —C(═O)S(C₁₋₆ alkyl), —C(═S)SC₁₋₆ alkyl, —SC(═S)SC₁₋₆alkyl, —P(═O)₂(C₁₋₆ alkyl), P(═O)(C₁₋₆ alkyl)₂, —OP(═O)(C₁₋₆ alkyl)₂,—OP(═O)(OC₁₋₆ alkyl)₂, C₁₋₆ alkyl, C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂alkynyl, C₃₋₁₀ carbocyclyl, C₆₋₁₀ aryl, 3-10 membered heterocyclyl, 5-10membered heteroaryl; or two geminal R²² substituents can be joined toform ═O or ═S; wherein X⁻ is a counterion.
 13. The compound according toclaim 12, wherein R¹⁵ is selected from fluoro (—F), bromo (—Br), chloro(—Cl), and iodo (—I), —OR¹⁶, —C(═O)N(R¹⁸)₂, —SO₂N(R¹⁸)₂, C₁₋₁₀ alkyl,C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₆₋₁₄ aryl, and 5-14membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, aryl, andheteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R¹⁹groups.
 14. The compound according to claim 12, wherein Y¹ is S, Y³ isN, and Y² and Y⁴ are independently CH or CR¹⁵.
 15. The compoundaccording to claim 14, wherein the compound is of the formula:

or a pharmaceutically acceptable form thereof.
 16. The compoundaccording to claim 12, wherein Y¹ is S and each Y², Y³ and Y⁴ isindependently CH or CR¹⁵.
 17. The compound according to claim 16,wherein the compound is of the formulae:

or a pharmaceutically acceptable form thereof.
 18. The compoundaccording to claim 1, wherein G is selected from —Cl, —Br, —I, —OR^(e),—ONR^(f)R^(e), —ONR^(f)(C═O)R^(e), —ONR^(f)SO₂R^(e), —ONR^(f)PO₂R^(e),—ONR^(f)PO₂OR^(e), —SR^(e), —OSO₂R^(e), —NR^(f)SO₂R^(e), —OPO₂R^(e),—OPO₂OR^(e), —NR^(f)PO₂R^(e), —NR^(f)PO₂OR^(e), —OPO₂NR^(f)R^(e),—O(C═O)R^(e), —O(C═O)OR^(e), —NR^(f)R^(e), —NR^(f)(C═O)R^(e),—NR^(f)(C═O)OR^(e), —O(C═O)NR^(f)R^(e), —NR^(f)(C═NR^(f))NR^(f)R^(e),—O(C═NR^(f))NR^(f)R^(e), —NR^(f)(C═NR^(f))OR^(e), and—[N(R^(f))₂R^(e)]⁺X⁻ wherein X⁻ is a counterion.
 19. The compoundaccording to claim 18, wherein G is —OR^(e).
 20. The compound accordingto claim 19, wherein R^(e) is C₆₋₁₄ aryl.
 21. The compound according toclaim 20, wherein R^(e) is phenyl.
 22. The compound according to claim21, wherein R^(e) is a monosubstituted phenyl.
 23. The compoundaccording to claim 21, wherein R^(e) is a phenyl group of the formula:

wherein: x is 0, 1, 2, 3, 4 or 5, and each R^(h) is, independently,selected from fluoro (—F), bromo (—Br), chloro (—Cl), and iodo (—I),—CN, —NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR^(i), —ON(R^(k))₂, —N(R^(k))₂,—N(R^(k))₃—N(OR^(j))R^(k), —SH, —SSR^(j), —C(═O)R^(i), —CO₂H, —CHO,—CO₂R^(i), —OC(═O)R^(i), —OCO₂R^(i), —C(═O)N(R^(k))₂, —OC(═O)N(R^(k))₂,—NR^(k)C(═O)R^(i), —NR^(k)CO₂R^(i), —NR^(k)C(═O)N(R^(k))₂,—C(═NR^(k))—C(═NR^(k))OR^(i), —OC(═NR^(k))R^(i), —OC(═NR^(k))OR^(i),—C(═NR^(k))N(R^(k))₂, —OC(═NR^(k))N(R^(k))₂, —NR^(k)C(═NR^(k))N(R^(k))₂,—C(═O)NR^(k)SO₂R^(i), —NR^(k)SO₂R^(i), —SO₂N(R^(k))₂, —SO₂R^(i),—SO₂OR^(i), —OSO₂R^(i), —S(═O)R^(i), —OS(═O)R^(i), —Si(R^(i))₃,—OSi(R^(i))₃—C(═S)N(R^(k))₂, —C(═O)SR^(i), —C(═S)SR^(i), —SC(S)SR^(i),—P(═O)₂R^(i), —OP(═O)₂R^(i), —P(═O)(R^(i))₂, —OP(═O)(R^(i))₂,—OP(═O)(OR^(j))₂, —P(═O)₂N(R^(k))₂, —OP(═O)₂N(R^(k))₂, —P(═O)(NR^(k))₂,—OP(═O)(NR^(k))₂, —NR^(k)P(═O)(OR^(j))₂, —NR^(k)P(═O)(NR^(k))₂,—P(R^(j))₂, —P(R^(j))₃, —OP(R^(j))₂, —OP(R^(j))₃, —B(OR^(j))₂,—BR^(i)(OR^(j)), C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, C₃₋₁₄ carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3, 4, or 5 R^(m) groups; each instance ofR^(i) is, independently, selected from C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl,C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocyclyl, 3-14 memberedheterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroaryl, wherein eachalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroarylis independently substituted with 0, 1, 2, 3, 4, or 5 R^(m) groups; eachinstance of R^(k) is, independently, selected from hydrogen, —OH,—OR^(i), —N(R^(j))₂, —CN, —C(═O)R^(i), —C(═O)N(R^(j))₂, —CO₂R^(i),—SO₂R^(i), —C(═NR^(j))OR^(i), —C(═NR^(j))N(R^(j))₂, —SO₂N(R^(j))₂,—SO₂R^(j), —SO₂OR^(j), —SOR^(i), —C(═S)N(R^(j))₂, —C(═O)SR^(j),—C(═S)SR^(j), —P(═O)₂R^(i), —P(═O)(R^(i))₂, —P(═O)₂N(R^(j))₂,—P(═O)(NR^(i))₂, C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, C₃₋₁₀ carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and5-14 membered heteroaryl, or two R^(j) groups attached to an N atom arejoined to form a 3-14 membered heterocyclyl or 5-14 membered heteroarylring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl,aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or5 R^(m) groups; each instance of is, independently, selected fromhydrogen, C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl,C₃₋₁₀ carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14membered heteroaryl, or two R^(j) groups attached to an N atom arejoined to form a 3-14 membered heterocyclyl or 5-14 membered heteroarylring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl,aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or5 R^(m) groups; each instance of R^(m) is, independently, selected fromfluoro (—F), bromo (—Br), chloro (—Cl), and iodo (—I), —CN, —NO₂, —N₃,—SO₂H, —SO₃H, —OH, —OR^(o), —ON(R^(n))₂, —N(R^(n))₂, —N(R^(n))₃ ⁺X⁻,—N(OR^(o))R^(n), —SH, —SR^(o), —SSR^(o), —C(═O)R^(o), —CO₂H, —CO₂R^(o),—OC(═O)R^(o), —OCO₂R^(o), —C(═O)N(R^(n))₂, —OC(═O)N(R^(n))₂,—NR^(n)C(═O)R^(o), —NR^(n)CO₂R^(o), —NR^(n)C(═O)N(R^(n))₂,—C(═NR^(n))OR^(o), —OC(═NR^(n))R^(o), —OC(═NR^(n))OR^(o),—C(═NR^(n))N(R^(n))₂, —OC(═NR^(n))N(R^(n))₂, —NR^(n)C(═NR^(n))N(R^(n))₂,—NR^(n)SO₂R^(o), —SO₂N(R^(n))₂, —SO₂R^(o), —SO₂OR^(o), —OSO₂R^(o),—S(═O)R^(o), —Si(R^(o))₃, —OSi(R^(o))₃, —C(═S)N(R^(n))₂, —C(═O)SR^(o),—C(═S)SR^(o), —SC(═S)SR^(o), —P(═O)₂R^(o), —P(═O)(R^(o))₂,—OP(═O)(R^(o))₂, —OP(═O)(OR^(o))₂, C₁₋₆ alkyl, C₁₋₆ perhaloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl, 3-14 membered heterocyclyl,C₆₋₁₄ aryl, 5-14 membered heteroaryl, wherein each alkyl, alkenyl,alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl isindependently substituted with 0, 1, 2, 3, 4, or 5 R^(p) groups, or twogeminal R^(m) substituents can be joined to form ═O or ═S; each instanceof R^(o) is, independently, selected from C₁₋₆ alkyl, C₁₋₆ perhaloalkyl,C₂₋₆ alkenyl, C₂ alkynyl, C₃₋₁₀ carbocyclyl, C₆₋₁₀ aryl, 3-10 memberedheterocyclyl, and 3-10 membered heteroaryl, wherein each alkyl, alkenyl,alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl isindependently substituted with 0, 1, 2, 3, 4, or 5 R^(p) groups; eachinstance of is, independently, selected from hydrogen, C₁₋₆ alkyl, C₁₋₆perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl, 3-10membered heterocyclyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl, or twogroups attached to an N atom are joined to form a 3-14 memberedheterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl,alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl isindependently substituted with 0, 1, 2, 3, 4, or 5 R^(p) groups; andeach instance of R^(p) is, independently, fluoro (—F), bromo (—Br),chloro (—Cl), and iodo (—I), —CN, —NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OC₁₋₆alkyl, —ON(C₁₋₆ alkyl)₂, alkyl)₂, alkyl)₃X, —NH(C₁₋₆ alkyl)₂X, —NH₂(C₁₋₆alkyl)X, —NH₃X, —N(OC₁₋₆ alkyl)(C₁₋₆ alkyl), —N(OH)(C₁₋₆ alkyl),—NH(OH), —SH, —SC₁₋₆ alkyl, —SS(C₁₋₆ alkyl), —C(═O)(C₁₋₆ alkyl), —CO₂H,—CO₂ (C₁₋₆ alkyl), —OC(═O)(C₁₋₆ alkyl), —OCO₂(C₁₋₆ alkyl), —C(═O)NH₂,—C(═O)N(C₁₋₆ alkyl)₂, —OC(═O)NH(C₁₋₆ alkyl), —NHC(═O)(C₁₋₆ alkyl),—N(C₁₋₆ alkyl)C(═O)(C₁₋₆ alkyl), —NHCO₂(C₁₋₆ alkyl), —NHC(═O)N(C₁₋₆alkyl)₂, —NHC(═O)NH(C₁₋₆ alkyl), —NHC(═O)NH₂, —C(═NH)O(C₁₋₆ alkyl),—OC(═NH)(C₁₋₆ alkyl), —OC(═NH)OC₁₋₆ alkyl, —C(═NH)N(C₁₋₆ alkyl)₂,—C(═NH)NH(C₁₋₆ alkyl), —C(═NH)NH₂, —OC(═NH)N(C₁₋₆ alkyl)₂,—OC(NH)NH(C₁₋₆ alkyl), —O(NH)NH₂, —NHC(NH)N(C₁₋₆ alkyl)₂, —NHC(═NH)NH₂,—NHSO₂ (C₁₋₆ alkyl), —SO₂N(C₁₋₆ alkyl)₂, —SO₂NH(C₁₋₆ alkyl), —SO₂NH₂,—SO₂C₁₋₆ alkyl, —SO₂OC₁₋₆ alkyl, —OSO₂C₁₋₆ alkyl, —SOC₁₋₆ alkyl,—Si(C₁₋₆ alkyl)₃, alkyl)₃ —C(═S)N(C₁₋₆ alkyl)₂, C(═S)NH(C₁₋₆ alkyl),C(═S)NH₂, —C(═O)S(C₁₋₆ alkyl), —C(═S)SC₁₋₆ alkyl, —SC(═S)SC₁₋₆ alkyl,—P(═O)₂(C₁₋₆ alkyl), —P(═O)(C₁₋₆ alkyl)₂, —OP(═O)(C₁₋₆ alkyl)₂,—OP(═O)(OC₁₋₆ alkyl)₂, C₁₋₆ alkyl, C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ carbocyclyl, C₆₋₁₄ aryl, 3-14 membered heterocyclyl, 5-14membered heteroaryl; or two geminal R^(p) substituents can be joined toform ═O or ═S; wherein X⁻ is a counterion.
 24. The compound according toclaim 23, wherein R^(h) is selected from fluoro (—F), bromo (—Br),chloro (—Cl), and iodo (—I), —CN, —NO₂, —OH, —OR^(i), —SR^(i),—N(R^(k))₂, —N(R^(k))₃ ⁺X⁻, —C(═O)R^(i), —CO₂R^(i), —CO₂H, —OC(═O)R^(i),—OCO₂R^(i), —C(═O)N(R^(k))₂, —OC(═O)N(R^(k))₂, —NR^(k)C(═O)R^(i),—NR^(k)CO₂R^(i), —NR^(k)C(═O)N(R^(k))₂, —C(═O)NR^(k)SO₂R^(i),—NR^(k)SO₂R^(i), —SO₂N(R)₂, —SO₂Ri, C₁₋₁₀ alkyl, C₆ aryl, and 5-6membered heteroaryl, wherein each alkyl, aryl, and heteroaryl isindependently substituted with 0, 1, 2, 3 or 4 R^(m) groups; and whereinX⁻ is a counterion.
 25. The compound according to claim 24, whereinR^(h) is selected from —C(═O)R^(i), —CO₂H, —SO₂R^(i), and 5-memberedheteroaryl independently substituted with 0 or 1 R^(m) groups.
 26. Thecompound according to claim 25, wherein the 5-membered heteroaryl isselected from pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl,oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl,thiadiazolyl, and tetrazolyl.
 27. The compound according to claim 21,wherein the phenyl group is a monosubstituted phenyl group of any one ofthe formulae:


28. The compound according to claim 21, wherein the phenyl group is adisubstituted phenyl group of any one of the formulae:


29. The compound according to claim 19, wherein G is —OR^(e) is selectedfrom:


30. The compound according to claim 19, wherein R^(e) is 5-14 memberedheteroaryl.
 31. The compound according to claim 30, wherein R^(e) is a6-membered heteroaryl.
 32. The compound according to claim 31, whereinR^(e) is a pyrindinyl group.
 33. The compound according to claim 32,wherein R^(e) is a monosubstituted pyrindinyl group.
 34. The compoundaccording to claim 32, wherein R^(e) is a 3-pyridinyl group.
 35. Thecompound according to claim 32, wherein R^(e) is a pyrindinyl group ofthe formula: wherein x is 0, 1, 2, 3 or 4, and

each R^(h) is, independently, selected from fluoro (—F), bromo (—Br),chloro (—Cl), and iodo (—I), —CN, —NO₂, —N₃, —SO₂H, —SO₃H, —OH,—ON(R^(k))₂, —N(R^(k))₂, —N(R^(k))₃ ⁺X⁻, —N(OR^(j))R^(k), —SH, —SR^(i),—SSR^(j), —C(═O)R^(i), —CO₂H, —CHO, —CO₂R^(i), —OC(═O)R^(i), —OCO₂R^(i),—C(═O)N(R^(k))₂, —OC(═O)N(R^(k))₂, —NR^(k)C(═O)W, —NR^(k)CO₂W,—NR^(k)C(═O)N(R^(k))₂, —C(═NR^(k))—C(═NR^(k))OR^(i), —OC(═NR^(k))W,—OC(═NR^(k))OR^(i), —C(═NR^(k))N(R^(k))₂, —OC(═NR^(k))N(R^(k))₂,—NR^(k)C(═NR^(k))N(R^(k))₂, —C(═O)NR^(k)SO₂Ri, —NR^(k)SO₂R^(i),—SO₂N(R^(k))₂, —SO₂R^(i), —SO₂OR^(i), —OSO₂R^(i), —S(═O)R^(i),—OS(═O)R^(i), —Si(R^(i))₃, —OSi(R^(i))₃—C(═S)N(R^(k))₂, —C(═O)SR^(i),—C(═S)SR^(i), —SC(S)SR^(i), —P(═O)₂W, —OP(═O)₂R^(i), —P(═O)(R^(i))₂,—OP(═O)(R^(i))₂, —OP(═O)(OR^(i))₂, —P(═O)₂N(R^(k))₂, —OP(═O)₂N(R^(k))₂,—P(═O)(NR^(k))₂, —OP(═O)(NR^(k))₂, —NR^(k)P(═O)(OR^(j))₂,—NR^(k)P(═O)(NR^(k))₂, —P(R^(j))₂, —P(R)₃, —OP(R)₂, —OP(R)₃,—B(OR^(j))₂, —BR^(i)(OR^(j)), C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₄ carbocyclyl, 3-14 membered heterocyclyl,C₆₋₁₄ aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl,alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl isindependently substituted with 0, 1, 2, 3, 4, or 5 R^(m) groups; eachinstance of R^(i) is, independently, selected from C₁₋₁₀ alkyl, C₁₋₁₀perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocyclyl, 3-14membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroaryl, whereineach alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^(m)groups; each instance of R^(k) is, independently, selected fromhydrogen, —OH, —OR^(i), —N(R^(j))₂, —CN, —C(═O)R^(i), —C(═O)N(R^(j))₂,—CO₂R^(i), —SO₂R^(i), —C(═NR^(j))OR^(i), —C(═NR^(j))N(R^(j))₂,—SO₂N(R^(j))₂, —SO₂R^(j), —SO₂OR^(j), —SOR^(i), —C(═S)N(R^(j))₂,—C(═O)SR^(j), —C(═S)SR^(j), —P(═O)₂R^(i), —P(═O)(R^(i))₂,—P(═O)₂N(R^(j))₂, —(═O)(NR^(j))₂, C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocyclyl, 3-14 membered heterocyclyl,C₆₋₁₄ aryl, and 5-14 membered heteroaryl, or two R^(j) groups attachedto an N atom are joined to form a 3-14 membered heterocyclyl or 5-14membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3, 4, or 5 R^(m) groups; each instance of is,independently, selected from hydrogen, C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl,C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocyclyl, 3-14 memberedheterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroaryl, or two R^(j)groups attached to an N atom are joined to form a 3-14 memberedheterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl,alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl isindependently substituted with 0, 1, 2, 3, 4, or 5 R^(m) groups; eachinstance of R^(m) is, independently, selected from fluoro (—F), bromo(—Br), chloro (—Cl), and iodo (—I), —CN, —NO₂, —N₃, —SO₂H, —SO₃H, —OH,—OR^(o), —ON(R^(n))₂, —N(R^(n))₂, —N(R^(n))₃ ⁺X⁻, —N(OR^(o)R^(n), —SH,—SR^(o), —SSR^(o), —C(═O)R^(o), —CO₂H, —CO₂R^(o), —OC(═O)R^(o),—OCO₂R^(o), —C(═O)N(R^(n))₂, —OC(═O)N(R^(n))₂, —NR^(n)C(═O)R^(o),—NR^(n)CO₂R^(o), —NR^(n)C(═O)N(R^(n))₂, —C(═NR^(n))OR^(o),—OC(═NR^(n))R^(o), —OC(═NR^(n))OR^(o), —C(═NR^(n))N(R^(n))₂,—OC(═NR^(n))N(R^(n))₂, —NR^(n)C(═NR^(n))N(R^(n))₂, —NR^(n)SO₂R^(o),—SO₂N(R^(n))₂, —SO₂R^(o), —SO₂OR^(o), —OSO₂R^(o), —S(═O)R^(o),—Si(R^(o))₃, —OSi(R^(o))₃, —C(═S)N(R^(n))₂, —C(═O)SR^(o), —C(═S)SR^(o),—SC(═S)SR^(o), —P(═O)₂R^(o), —P(═O)(R^(o))₂, —OP(═O)(R^(o))₂,—OP(═O)(OR^(o))₂, C₁₋₆ alkyl, C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, 5-14membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl,heterocyclyl, aryl, and heteroaryl is independently substituted with 0,1, 2, 3, 4, or 5 R^(p) groups, or two geminal R^(m) substituents can bejoined to form ═O or ═S; each instance of R^(o) is, independently,selected from C₁₋₆ alkyl, C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂ alkynyl,C₃₋₁₀ carbocyclyl, C₆₋₁₀ aryl, 3-10 membered heterocyclyl, and 3-10membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl,heterocyclyl, aryl, and heteroaryl is independently substituted with 0,1, 2, 3, 4, or 5 R^(p) groups; each instance of R^(n) is, independently,selected from hydrogen, C₁₋₆ alkyl, C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl, 3-10 membered heterocyclyl, C₆₋₁₀ aryland 5-10 membered heteroaryl, or two R^(n) groups attached to an N atomare joined to form a 3-14 membered heterocyclyl or 5-14 memberedheteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl,heterocyclyl, aryl, and heteroaryl is independently substituted with 0,1, 2, 3, 4, or 5 R^(p) groups; and each instance of R^(p) is,independently, fluoro (—F), bromo (—Br), chloro (—Cl), and iodo (—I),—CN, —NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OC₁₋₆ alkyl, —ON(C₁₋₆ alkyl)₂,—N(C₁₋₆ alkyl)₂, —N(C₁₋₆ alkyl)₃X, —NH(C₁₋₆ alkyl)₂X, —NH₂(C₁₋₆ alkyl)X,—NH₃X, —N(OC₁₋₆ alkyl)(C₁₋₆ alkyl), —N(OH)(C₁₋₆ alkyl), —NH(OH), —SH,—SC_(is) alkyl, —SS(C₁₋₆ alkyl), —C(═O)(C₁₋₆ alkyl), —CO₂H, —CO₂ (C₁₋₆alkyl), —OC(═O)(C₁₋₆ alkyl), —OCO₂ (C₁₋₆ alkyl), —C(═O)NH₂, —C(═O)N(C₁₋₆alkyl)₂, —OC(═O)NH(C₁₋₆ alkyl), —NHC(═O)(C₁₋₆ alkyl), —N(C₁₋₆alkyl)C(═O)(C₁₋₆ alkyl), —NHCO₂(C₁₋₆ alkyl), —NHC(═O)N(C₁₋₆ alkyl)₂,—NHC(═O)NH(C₁₋₆ alkyl), —NHC(═O)NH₂, —C(═NH)O(C₁₋₆ alkyl), —OC(═NH)(C₁₋₆alkyl), —OC(═NH)OC₁₋₆ alkyl, —C(═NH)N(C₁₋₆ alkyl)₂, —C(═NH)NH(C₁₋₆alkyl), —C(═NH)NH₂, —OC(═NH)N(C₁₋₆ alkyl)₂, —OC(NH)NH(C₁₋₆ alkyl),—OC(NH)NH₂, —NHC(NH)N(C₁₋₆ alkyl)₂, —NHC(═NH)NH₂, —NHSO₂ (C₁₋₆ alkyl),—SO₂N(C₁₋₆ alkyl)₂, —SO₂NH(C₁₋₆ alkyl), —SO₂NH₂, —SO₂C₁₋₆ alkyl,—SO₂OC₁₋₆ alkyl, —OSO₂C₁₋₆ alkyl, —SOC₁₋₆ alkyl, —Si(C₁₋₆ alkyl)₃,—OSi(C₁₋₆ alkyl)₃—C(═S)N(C₁₋₆ alkyl)₂, C(═S)NH(C₁₋₆ alkyl), C(═S)NH₂,—C(═O)S(C₁₋₆ alkyl), —C(═S)SC₁₋₆ alkyl, —SC(═S)SC₁₋₆ alkyl, —P(═O)₂(C₁₋₆alkyl), —P(═O)(C₁₋₆ alkyl)₂, —OP(═O)(C₁₋₆ alkyl)₂, —OP(═O)(OC₁₋₆alkyl)₂, C₁₋₆ alkyl, C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂ alkynyl, C₃₋₁₀carbocyclyl, C₆₋₁₄ aryl, 3-14 membered heterocyclyl, 5-14 memberedheteroaryl; or two geminal R^(p) substituents can be joined to form ═Oor ═S; wherein X⁻ is a counterion.
 36. The compound according to claim35, wherein R^(h) is selected from fluoro (—F), bromo (—Br), chloro(—Cl), and iodo (—I), —CN, —NO₂, —OH, —OR^(i), —SR^(i), —N(R^(k))₂,—N(R^(k))₃—C(═O)R^(i), —CO₂R^(i), —CO₂H, —OC(═O)R^(i), —OCO₂R^(i),—C(═O)N(R^(k))₂, —OC(═O)N(R^(i))₂, —NR^(k)C(═O)R^(i), —NR^(k)CO₂R^(i),—NR^(k)C(═O)N(R^(k))₂, —C(═O)NR^(k)SO₂R^(i), —NR^(k)SO₂R^(i),—SO₂N(R^(k))₂, —SO₂Ri, C₁₋₁₀ alkyl, C₆ aryl, and 5-6 memberedheteroaryl, wherein each alkyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3 or 4 R^(m) groups; and wherein X⁻ is acounterion.
 37. The compound according to claim 36, wherein R^(h) isselected from —C(═O)R^(i), —CO₂H, —SO₂R^(i), and 5-membered heteroarylindependently substituted with 0 or 1 R^(m) groups.
 38. The compoundaccording to claim 37, wherein the 5-membered heteroaryl is selectedfrom pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl,thiadiazolyl, and tetrazolyl.
 39. The compound according to claim 35,wherein the pyridinyl group is a 3-pyridinyl group of the formulae:


40. The compound according to claim 19, wherein G is —OR^(e) is selectedfrom:


41. The compound according to claim 1, wherein the compound issubstantially enantiomerically pure.
 42. A pharmaceutical compositioncomprising a compound of claim 1, or a pharmaceutically acceptable formthereof, and a pharmaceutically acceptable excipient.
 43. A method oftreating an FAAH-mediated condition comprising administering to asubject in need thereof a therapeutically effective amount of a compoundof claim 1 or a pharmaceutically acceptable form thereof.
 44. The methodaccording to claim 43, wherein the FAAH-mediated condition is selectedfrom a painful condition, an inflammatory condition, an immune disorder,a disorder of the central nervous system, a metabolic disorder, acardiac disorder and glaucoma.
 45. The method according to claim 44,wherein the FAAH-mediated condition is a painful condition selected fromneuropathic pain, central pain, deafferentiation pain, chronic pain,post-operative pain, pre-operative pain, nociceptive pain, acute pain,non-inflammatory pain, inflammatory pain, pain associated with cancer,wound pain, burn pain, pain associated with medical procedures, painresulting from pruritus, painful bladder syndrome, pain associated withpremenstrual dysphoric disorder, pain associated with premenstrualsyndrome, pain associated with chronic fatigue syndrome, pain associatedwith pre-term labor, pain associated withdrawal symptoms from drugaddiction, joint pain, arthritic pain, lumbosacral pain,musculo-skeletal pain, headache, migraine, muscle ache, lower back pain,neck pain, toothache dental/maxillofacial pain and visceral pain. 46.The method according to claim 44, wherein the FAAH-mediated condition isan inflammatory condition or an immune disorder.
 47. The methodaccording to claim 46, wherein the inflammatory condition or immunedisorder is a gastrointestinal disorder.
 48. The method according toclaim 46, wherein the inflammatory condition or immune disorder is askin condition.
 49. The method according to claim 44, wherein theFAAH-mediated condition is a disorder of the central nervous systemselected from neurotoxicity and/or neurotrauma, stroke, multiplesclerosis, spinal cord injury, epilepsy, a mental disorder, a sleepcondition, a movement disorder, nausea and/or emesis, amyotrophiclateral sclerosis, Alzheimer's disease and drug addiction
 50. The methodaccording to claim 44, wherein the FAAH-mediated condition is ametabolic disorder selected from a wasting condition or anobesity-related condition or complication thereof.
 51. The methodaccording to claim 44, wherein the FAAH-mediated condition is a cardiacdisorder selected from hypertension, circulatory shock, myocardialreperfusion injury and atherosclerosis.
 52. The method according toclaim 44, wherein the FAAH-mediated condition is glaucoma.